AU2017272272A1 - Use of microvesicles in diagnosis, prognosis and treatment of medical diseases and conditions - Google Patents

Abstract

The presently disclosed subject matter is directed to methods of aiding diagnosis, prognosis, monitoring and evaluation of a disease or other medical condition in a' subject by detecting a biomarker in microvesicles isolated from a biological, sample from the subject. Moreover, disclosed subject matter is directed to methods of diagnosis, monitoring a disease by determining the concentration of microvesicles within a biological sample; methods of delivering a nucleic acid or protein to a target all by administering microvesicles that contain said nucleic acid or protein; methods for performing a body fluid transfusion by introducing a microvesicle-free or microvesicle enriched fluid fraction into a patient.

Description

invention was made with Government support under grants NCI CA86355 and NCI CA69246 awarded by the National Cancer Institute. The Government has certain rights in the invention.

FIELD OF THE INVENTION [0003] The present invention relates to the fields of medical diagnosis, patient monitoring, treatment efficacy evaluation, nucleic acid and protein delivery, and blood transfusion.

BACKGROUND OF THE INVENTION [0004] Glioblastomas are highly malignant brain tumors with a poor prognosis despite intensive research and clinical efforts (Louis et al., 2007). The invasive nature of this tumor makes complete surgical resection impossible and the median survival time is only about 15 months (Stupp et al., 2005). Glioblastoma cells as well as many other tumor cells have a remarkable ability to mold their stromal environment to their own advantage. Tumor cells directly alter surrounding normal cells to facilitate tumor cell growth, invasion, chemoresistance, immune-evasion and metastasis (Mazzocca et al., 2005; Muerkoster et al., 2004; Singer et al., 2007). The tumor cells also hijack the normal vasculature and stimulate rapid formation of new blood vessels to supply the tumor with nutrition (Carmeliet and Jain, 2000). Although the immune system can initially suppress tumor growth, it is often progressively blunted by tumor activation of immunosuppressive pathways (Gabrilovich, 2007).

[0005] Small microvesicles shed by cells are known as exosomes (Thery et al., 2002). Exosomes are reported as having a diameter of approximately 30-100 nm and are shed from many different cell types under both normal and pathological conditions (Thery et al., 2002). These microvesicles were first described as a mechanism to discard transferrin-receptors

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2017272272 07 Dec 2017 from the cell surface of maturing reticulocytes (Pan and Johnstone, 1983). Exosomes are formed through inward budding of endosomal membranes giving rise to intracellular multivesicular bodies (MVB) that later fuse with the plasma membrane, releasing the exosomes to the exterior (Thery et al., 2002). However, there is now evidence for a more direct release of exosomes. Certain cells, such as Jurkat T-cells, are said to shed exosomes directly by outward budding of the plasma membrane (Booth et al., 2006). All membrane vesicles shed by cells are referred to herein collectively as micro vesicles.

[0006] Microvesicles in Drosophila melanogaster, so called argosomes, are said to contain morphogens such as Wingless protein and to move over large distances through the imaginal disc epithelium in developing Drosophila melanogaster embryos (Greco et al., 2001). Microvesicles found in semen, known as prostasomes, are stated to have a wide range of functions including the promotion of sperm motility, the stabilization of the acrosome reaction, the facilitation of immunosuppression and the inhibition of angiogenesis (Delves et al., 2007). On the other hand, prostasomes released by malignant prostate cells are said to promote angiogenesis. Microvesicles are said to transfer proteins (Mack et al., 2000) and recent studies state that microvesicles isolated from different cell lines can also contain messenger RNA (mRNA) and microRNA (miRNA) and can transfer mRNA to other cell types (Baj-Krzyworzeka et al., 2006; Valadi et al., 2007).

[0007] Microvesicles derived from B-cells and dendritic cells are stated to have potent immuno-stimulatory and antitumor effects in vivo and have been used as antitumor vaccines (Chaput et al., 2005). Dendritic cell-derived microvesicles are stated to contain the costimulatory proteins necessary for T-cell activation, whereas most tumor cell-derived microvesicles do not (Wieckowski and Whiteside, 2006). Microvesicles isolated from tumor cells may act to suppress the immune response and accelerate tumor growth (Clayton et al., 2007; Liu et al., 2006a). Breast cancer microvesicles may stimulate angiogenesis, and platelet-derived micro vesicles may promote tumor progression and metastasis of lung cancer cells (Janowska-Wieczorek et al., 2005; Millimaggi et al., 2007).

[0008] Cancers arise through accumulation of genetic alterations that promote unrestricted cell growth. It has been stated that each tumor harbors, on average, around 50-80 mutations that are absent in non-tumor cells (Jones et al., 2008; Parsons et al., 2008; Wood et al., 2007). Current techniques to detect these mutation profiles include the analysis of biopsy samples and the non-invasive analysis of mutant tumor DNA fragments circulating in bodily fluids such as blood (Diehl et al., 2008). The former method is invasive, complicated and

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2017272272 07 Dec 2017 possibly harmful to subjects. The latter method inherently lacks sensitivity due to the extremely low copy number of mutant cancer DNA in bodily fluid (Gormally et al., 2007). Therefore, one challenge facing cancer diagnosis is to develop a diagnostic method that can detect tumor cells at different stages non-invasively, yet with high sensitivity and specificity. It has also been stated that gene expression profiles (encoding mRNA or microRNA) can distinguish cancerous and non-cancerous tissue (Jones et al., 2008; Parsons et al., 2008; Schetter et al., 2008). However, current diagnostic techniques to detect gene expression profiles require intrusive biopsy of tissues. Some biopsy procedures cause high risk and are potentially harmful. Moreover, in a biopsy procedure, tissue samples are taken from a limited area and may give false positives or false negatives, especially in tumors which are heterogeneous and/or dispersed within normal tissue. Therefore, a non-intrusive and sensitive diagnostic method for detecting biomarkers would be highly desirable.

SUMMARY OF THE INVENTION [0009] In general, the invention is a novel method for detecting in a subject the presence or absence of a variety of biomarkers contained in micro vesicles, thereby aiding the diagnosis, monitoring and evaluation of diseases, other medical conditions, and treatment efficacy associated with microvesicle biomarkers.

[0010] One aspect of the invention are methods for aiding in the diagnosis or monitoring of a disease or other medical condition in a subject, comprising the steps of: a) isolating a microvesicle fraction from a biological sample from the subject; and b) detecting the presence or absence of a biomarker within the microvesicle fraction, wherein the biomarker is associated with the disease or other medical condition. The methods may further comprise the step or steps of comparing the result of the detection step to a control (e.g., comparing the amount of one or more biomarkers detected in the sample to one or more control levels), wherein the subject is diagnosed as having the disease or other medical condition (e.g., cancer) if there is a measurable difference in the result of the detection step as compared to a control.

[0011] Another aspect of the invention is a method for aiding in the evaluation of treatment efficacy in a subject, comprising the steps of: a) isolating a microvesicle fraction from a biological sample from the subject; and b) detecting the presence or absence of a biomarker within the microvesicle fraction, wherein the biomarker is associated with the treatment efficacy for a disease or other medical condition. The method may further

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2017272272 07 Dec 2017 comprise the step of providing a series of a biological samples over a period of time from the subject. Additionally, the method may further comprise the step or steps of determining any measurable change in the results of the detection step (e.g., the amount of one or more detected biomarkers) in each of the biological samples from the series to thereby evaluate treatment efficacy for the disease or other medical condition.

[0012] In certain preferred embodiments of the foregoing aspects of the invention, the biological sample from the subject is a sample of bodily fluid. Particularly preferred body fluids are blood and urine.

[0013] In certain preferred embodiments of the foregoing aspects of the invention, the methods further comprise the isolation of a selective microvesicle fraction derived from cells of a specific type (e.g., cancer or tumor cells). Additionally, the selective microvesicle fraction may consist essentially of urinary micro vesicles.

[0014] In certain embodiments of the foregoing aspects of the invention, the biomarker associated with a disease or other medical condition is i) a species of nucleic acid; ii) a level of expression of one or more nucleic acids; iii) a nucleic acid variant; or iv) a combination of any of the foregoing. Preferred embodiments of such biomarkers include messenger RNA, microRNA, DNA, single stranded DNA, complementary DNA and noncoding DNA.

[0015] In certain embodiments of the foregoing aspects of the invention, the disease or other medical condition is a neoplastic disease or condition (e.g., glioblastoma, pancreatic cancer, breast cancer, melanoma and colorectal cancer), a metabolic disease or condition (e.g., diabetes, inflammation, perinatal conditions or a disease or condition associated with iron metabolism), a post transplantation condition, or a fetal condition.

[0016] Another aspect of the invention is a method for aiding in the diagnosis or monitoring of a disease or other medical condition in a subject, comprising the steps of a) obtaining a biological sample from the subject; and b) determining the concentration of microvesicles within the biological sample.

[0017] Yet another aspect of this invention is a method for delivering a nucleic acid or protein to a target cell in an individual comprising the steps of administering microvesicles which contain the nucleic acid or protein, or one or more cells that produce such microvesicles, to the individual such that the microvesicles enter the target cell of the individual. In a preferred embodiment of this aspect of the invention, microvesicles are delivered to brain cells.

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2017272272 07 Dec 2017 [0018] A further aspect of this invention is a method for performing bodily fluid transfusion (e.g., blood, serum or plasma), comprising the steps of obtaining a fraction of donor body fluid free of all or substantially all microvesicles, or free of all or substantially all microvesicles from a particular cell type (e.g., tumor cells), and introducing the microvesiclefree fraction to a patient. A related aspect of this invention is a composition of matter comprising a sample of body fluid (e.g., blood, serum or plasma) free of all or substantially all micro vesicles, or free of all or substantially all microvesicles from a particular cell type.

[0019] Another aspect of this invention is a method for performing bodily fluid transfusion (e.g., blood, serum or plasma), comprising the steps of obtaining a microvesicleenriched fraction of donor body fluid and introducing the microvesicle-enriched fraction to a patient. In a preferred embodiment, the fraction is enriched with microvesicles derived from a particular cell type. A related aspect of this invention is a composition of matter comprising a sample of bodily fluid (e.g., blood, serum or plasma) enriched with micro vesicles.

[0020] A further aspect of this invention is a method for aiding in the identification of new biomarkers associated with a disease or other medical condition, comprising the steps of obtaining a biological sample from a subject; isolating a microvesicle fraction from the sample; and detecting within the microvesicle fraction species of nucleic acid; their respective expression levels or concentrations; nucleic acid variants; or combinations thereof.

[0021] Various aspects and embodiments of the invention will now be described in detail. It will be appreciated that modification of the details may be made without departing from the scope of the invention. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0022] All patents, patent applications, and publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these documents.

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BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1. Glioblastoma cells produce microvesicles containing RNA.

(a) Scanning electron microscopy image of a primary glioblastoma cell (bar = 10 pm), (b) Higher magnification showing the microvesicles on the cell surface. The vesicles vary in size with diameters between around 50 nm and around 500 nm (bar = 1 pm), (c) Graph showing the amount of total RNA extracted from microvesicles that were either treated or not treated with RNase A. The amounts are indicated as the absorption (Abs, y-axis) of 260nm wavelength (x-axis). The experiments were repeated 5 times and a representative graph is shown, (d) Bioanalyzer data showing the size distribution of total RNA extracted from primary glioblastoma cells and (e) Bioanalyzer data showing the size distribution of total RNA extracted from micro vesicles isolated from primary glioblastoma cells. The 25 nt peak represents an internal standard. The two prominent peaks in (d) (arrows) represent 18S (left arrow) and 28S (right arrow) ribosomal RNA. The ribosomal peaks are absent from RNA extracted from microvesicles (e). (f) Transmission electron microscopy image of micro vesicles secreted by primary glioblastoma cells (bar = 100 nm).

FIGURE 2. Analysis of microvesicle RNA. FIGS. 2 (a) and 2 (b) are scatter plots of mRNA levels in microvesicles and mRNA levels in donor glioblastoma cells from two different experiments. Linear regressions show that mRNA levels in donor cells versus micro vesicles were not well correlated. FIGS. 2 (c) and 2 (d) are mRNA levels in two different donor cells or two different micro vesicle preparations. In contrast to FIGS. 2 (a) and 2 (b), linear regressions show that mRNA levels between donor cells FIG 2 (c) or between microvesicles FIG 2 (d) were closely correlated.

FIGURE 3. Analysis of microvesicle DNA.

a) GAPDH gene amplification with DNA templates from exosomes treated with DNase prior to nucleic acid extraction. The lanes are identified as follows:

1. lOObp MW ladder

2. Negative control

3. Genomic DNA control from GBM 20/3 cells

4. DNA from normal serum exosomes (tumor cell-free control)

5. Exosome DNA from normal human fibroblasts (NHF19)

6. Exosome DNA from primary medulloblastoma cells (D425)

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b) GAPDH gene amplification with DNA templates from exosomes without prior DNase treatment. The lanes are identified as follows:

1. lOObp MW ladder

2. DNA from primary melanoma cell 0105

3. Exosome DNA from melanoma 0105

4. Negative Control

5. cDNA from primary GBM 20/3 (positive control)

c) Human Endogenous Retrovirus K gene amplification. The lanes are identified as follows:

1. 100 bp MW ladder

2. Exosome DNA from medulloblastoma D425 a

3. Exosome DNA from medulloblasotma D425 b

4. Exosome DNA from normal human fibroblasts (NHF19)

5. Exosome DNA from normal human serum

6. Genomic DNA from GBM 20/3.

7. Negative Control

d) Tenascin C gene amplification. The lanes are listed identified follows:

1. lOObp MW ladder

2. Exosomes from normal human fibroblasts (NHF19)

3. Exosomes from serum (tumor cell free individual A)

4. Exosomes from serum (tumor cell free individual B)

5. Exosomes from primary medulloblastoma cell D425

e) Transposable Line 1 element amplification. The lanes are identified as follows:

1. lOObp MW ladder.

2. Exosome DNA from normal human serum.

3. Exosome DNA from normal human fibroblasts

4. Exosome DNA from medulloblastoma D425 a

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5. Exosome DNA from medulloblastoma D425 b

f) DNA is present in exosomes from D425 medulloblastoma cell. The lanes are identified as follows:

1. lOObp marker

2. D425 no DNase

3. D425 with DNase

4. lkb marker

g) Single stranded nucleic acid analysis using a RNA pico chip. Upper panel: purified DNA was not treated with DNase; lower panel: purified DNA was treated with DNase. The arrow in the upper panel refers to the detected nucleic acids. The peak at 25 nt is an internal standard.

h) Analysis of nucleic acids contained in exosomes from primary medulloblastoma D425. Upper panel: single stranded nucleic acids detected by a RNA pico chip. Lower panel: double stranded nucleic acids detected by a DNA 1000 chip. The arrow in the upper panel refers to the detected nucleic acids. The two peaks (15 and 1500 bp) are internal standards.

i) Analysis of exosome DNA from different origins using a RNA pico chip. Upper panel: DNA was extracted from exosomes from glioblastoma cells. Lower panel: DNA was extracted from exosomes from normal human fibroblasts.

FIGURE 4. Extracellular RNA extraction from serum is more efficient when a serum exosome isolation step is included, a) Exosome RNA from serum, b) Direct whole serum extraction, c) Empty well. Arrows refer to the detected RNA in the samples.

FIGURE 5. Comparison of gene expression levels between microvesicles and cells of origin. 3426 genes were found to be more than 5-fold differentially distributed in the microvesicles as compared to the cells from which they were derived (p-value <0.01).

FIGURE 6. Ontological analysis of micro vesicular RNAs. (a) Pie chart displays the biological process ontology of the 500 most abundant mRNA species in the micro vesicles.

(b) Graph showing the intensity of microvesicle RNAs belonging to ontologies related to tumor growth. The x-axis represents the number of mRNA transcripts present in the ontology. The median intensity levels on the arrays were 182.

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FIGURE 7. Clustering diagram of mRNA levels. Microarray data on the mRNA expression profiles in cell lines and exosomes isolated from the culture media of these cell lines were analyzed and clusters of expression profiles were generated. The labels of the RNA species are as follows:

20/3C-1: Glioblastoma 20/3 Cell RNA, array replicate 1

20/3C-2: Glioblastoma 20/3 Cell RNA, array replicate 2

11/5C: Glioblastoma 11/5 Cell RNA

0105C: Melanoma 0105 Cell RNA

0664C: Melanoma 0664 Cell RNA

0664 E-l: Melanoma 0664 exosome RNA, array replicate 1

0664 E-2: Melanoma 0664 exosome RNA, array replicate 2

0105E: Melanoma 0105 Exosome RNA

20/3E: Glioblastoma 20/3 Exosome RNA

11/5E-1: Glioblastoma 11/5 Exosomes, array replicate 1

11/5E-2: Glioblastoma 11/5 Exosomes, array replicate 2

GBM: glioblastoma. The scale refers to the distance between clusters.

FIGURE 8. Micro vesicles from serum contain microRNAs. Levels of mature miRNAs extracted from microvesicles and from glioblastoma cells from two different patients (GBM1 and GBM2) were analysed using quantitative miRNA RT-PCR. The cycle threshold (Ct) value is presented as the mean + SEM (n = 4).

FIGURE 9. Clustering diagram of microRNA levels. Microarray data on the microRNA expression profiles in cell lines and exosomes isolated from the culture media of these cell lines were analyzed and clusters of expression profiles were generated. The labels of the RNA species are as follows:

0664C-1: Melanoma 0664 Cell RNA, array replicate 1

0664C-2: Melanoma 0664 Cell RNA, array replicate 2

0105C-1: Melanoma 0105 Cell RNA, array replicate 1

0105C-2: Melanoma 0105 Cell RNA, array replicate 2

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20/3C-1: Glioblastoma 20/3 Cell RNA, array replicate 1

20/3C-2: Glioblastoma 20/3 Cell RNA, array replicate 2

11/5C-1: Glioblastoma 11/5 Cell RNA, array replicate 1

11/5C-2: Glioblastoma 11/5 Cell RNA, array replicate 2

11/5E-1: Glioblastoma 11/5 Exosomes, array replicate 1

11/5E-2: Glioblastoma 11/5 Exosomes, array replicate 2

20/3E-1: Glioblastoma 20/3 Exosome RNA, array replicate 1

20/3E-2: Glioblastoma 20/3 Exosome RNA, array replicate 2

0664 E: Melanoma 0664 exosome RNA

0105E-1: Melanoma 0105 Exosome RNA, array replicate 1

0105E-2: Melanoma 0105 Exosome RNA, array replicate 2

GBM: Glioblastoma. The scale refers to the distance between clusters.

FIGURE 10. The expression level of microRNA-21 in serum microvesicles is associated with glioma. Shown is a bar graph, normal control serum on the left, glioma serum on the right. Quantitative RT-PCR was used to measure the levels of microRNA-21 (miR21) in exosomes from serum of glioblastoma patients as well as normal patient controls. Glioblastoma serum showed a 5.4 reduction of the Ct-value, corresponding to an approximately 40 (2 )-fold increase of miR21. The miR21 levels were normalized to GAPDH in each sample (n=3).

FIGURE 11. Nested RT-PCR was used to detect EGFRvIII mRNA in tumor samples and corresponding serum exosomes. The wild type EGFR PCR product appears as a band at 1153 bp and the EGFRvIII PCR product appears as a band at 352 bp. RT PCR of GAPDH mRNA was included as a positive control (226 bp). Samples considered as positive for EGFRvIII are indicated with an asterisk. Patients 11, 12 and 14 showed only a weak amplification of EGFRvIII in the tumor sample, but it was evident when more samples were loaded.

FIGURE 12. Nested RT PCR of EGFRvIII was performed on microvesicles from 52 normal control serums. EGFRvIII (352 bp) was never found in the normal control serums. PCR of GAPDH (226 bp) was included as a control.

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FIGURE 13. Hepcidin mRNA can be detected within exosomes from human serum. A) Pseudo-gel generated by an Agilent Bioanalyzer. B) Raw plot generated by an Agilent Bioanalyser for the positive control (Sample 1). C) Raw plot generated by an Agilent Bioanalyser for the negative control (Sample 2). D) Raw plot generated by an Agilent Bioanalyser for the exosomes (Sample 3).

FIGURE 14. Urinary exosome isolation and nucleic acid identification within urinary exosomes. (a) Electron microscopy image of a multivesicular body (MVB) containing many small “exosomes” in a kidney tubule cell, (b) Electron microscopy image of isolated urinary exosomes. (c) Analysis of RNA transcripts contained within urinary exosomes by an Agilent Bioanalyzer. A broad range of RNA species were identified but both 18S and 28S ribosomal RNAs were absent, (d) Identification of various RNA transcripts in urinary exosomes by PCR. The transcripts thus identified were: Aquaporin 1 (AQP1); Aquaporin 2 (AQP2); Cubulin (CUBN); Megalin (LRP2); Arginine Vasopressin Receptor 2 (AVPR2); Sodium/Hydrogen Exchanger 3 (SLC9A3); V-ATPase BI subunit (ATP6V1B1); Nephrin (NPHS1); Podocin (NPHS2); and Chloride Channel 3 (CLCN3). From top to bottom, the five bands in the molecular weight (MW) lane correspond to 1000, 850, 650, 500, 400, 300 base pair fragments, (e) Bioanalyzer diagrams of exosomal nucleic acids from urine samples. The numbers refer to the numbering of human individuals, (f) Pseudogels depicting PCR products generated with different primer pairs using the nucleic acid extracts described in (e). House refers to actin gene and the actin primers were from Ambion (TX, USA). The +ve control refers to PCRs using human kidney cDNA from Ambion (TX, USA) as templates and the -ve control refers to PCRs without nucleic acid templates, (g) Pseudo-gel picture showing positive identification of actin gene cDNA via PCR with and without the DNase treatment of exosomes prior to nucleic acid extraction, (h) Bioanalyzer diagrams showing the amount of nucleic acids isolated from human urinary exosomes.

FIGURE 15. Analysis of prostate cancer biomarkers in urinary exosomes. (a) Gel pictures showing PCR products of the TMPRSS2-ERG gene and digested fragments of the PCR products. Pl and P2 refer to urine samples from patient 1 and patient 2, respectively.

For each sample, the undigested product is in the left lane and the digested product is in the right lane. MWM indicates lanes with MW markers. The sizes of the bands (both undigested and digested) are indicated on the right of the panel, (b) Gel pictures showing PCR products of the PCA3 gene and digested fragments of the PCR products. Pl, P2, P3 and P4 refer to urine samples from patient 1, patient 2, patient 3 and patient 4, respectively. For each

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2017272272 07 Dec 2017 sample, the undigested product is in the left lane and the digested product is in the right lane. MWM indicates lanes with MW markers. The sizes of the bands (both undigested and digested) are indicated on the right of the panel, (c) A summary of the information of the patients and the data presented in (a) and (b). TMERG refers to the TMPRSS2-ERG fusion gene.

FIGURE 16. BRAF mRNA is contained within micro vesicles shed by melanoma cells, (a) An electrophoresis gel picture showing RT-PCR products of BRAF gene amplification, (b) An electrophoresis gel picture showing RT-PCR products of GAPDH gene amplification. The lanes and their corresponding samples are as follows: Lane #1 - 100 bp Molecular Weight marker; Lane #2 - YUMEL-01-06 exo; Lane # 3 - YUMEL-01-06 cell; Lane #4 YUMEL-06-64 exo; Lane # 5. YUMEL-06-64 cell; Lane # 6. M34 exo; Lane # 7M34 cell; Lane # 8 - Fibroblast cell; Lane # 9 - Negative control. The reference term “exo” means that the RNA was extracted from exosomes in the culture media. The reference term “cell” means that the RNA was extracted from the cultured cells. The numbers following YUMEL refers to the identification of a specific batch of YUMEL cell line, (c) Sequencing results of PCR products from YUMEL-01-06 exo. The results from YUMEL-01-06 cell, YUMEL-06-64 exo and YUMEL-06-64 cell are the same as those from YUMEL-01-06 exo. (d) Sequencing results of PCR products from M34 exo. The results from M34 cell are the same as those from M34 exo.

FIGURE 17. Glioblastoma micro vesicles can deliver functional RNA to HBMVECs. (a) Purified microvesicles were labelled with membrane dye PKH67 (green) and added to HBMVECs. The microvesicles were internalised into endosome-like structures within an hour, (b) Microvesicles were isolated from glioblastoma cells stably expressing Glue. RNA extraction and RT-PCR of Glue and GAPDH mRNAs showed that both were incorporated into micro vesicles, (c) Microvesicles were then added to HBMVECs and incubated for 24 hours. The Glue activity was measured in the medium at 0, 15 and 24 hours after micro vesicle addition and normalized to Glue activity in micro vesicles. The results are presented as the mean + SEM (n = 4).

FIGURE 18. Glioblastoma micro vesicles stimulate angiogenesis in vitro and contain angiogenic proteins, (a) HBMVECs were cultured on Matrigel™ in basal medium (EBM) alone, or supplemented with GBM micro vesicles (EBM+MV) or angiogenic factors (EGM). Tubule formation was measured after 16 hours as average tubule length + SEM compared to cells grown in EBM (n = 6). (b) Total protein from primary glioblastoma cells and

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2017272272 07 Dec 2017 micro vesicles (MV) from these cells (1 mg each) were analysed on a human angiogenesis antibody array, (c) The arrays were scanned and the intensities analysed with the Image J software (n = 4).

FIGURE 19. Micro vesicles isolated from primary glioblastoma cells promote proliferation of the U87 glioblastoma cell line. 100,000 U87 cells were seeded in wells of a 24 well plate and allowed to grow for three days in (a) normal growth medium (DMEM-5% FBS) or (b) normal growth medium supplemented with 125 pg micro vesicles, (c) After three days, the non-supplemented cells had expanded to 480,000 cells, whereas the microvesiclesupplemented cells had expanded to 810,000 cells. NC refers to cells grown in normal control medium and MV refers to cells grown in medium supplemented with micro vesicles. The result is presented as the mean + SEM (n=6).

DETAILED DESCRIPTION OF THE INVENTION [0023] Micro vesicles are shed by eukaryotic cells, or budded off of the plasma membrane, to the exterior of the cell. These membrane vesicles are heterogeneous in size with diameters ranging from about lOnm to about 5000 nm. The small microvesicles (approximately 10 to lOOOnm, and more often 30 to 200 nm in diameter) that are released by exocytosis of intracellular multivesicular bodies are referred to in the art as “exosomes”. The methods and compositions described herein are equally applicable to microvesicles of all sizes; preferably 30 to 800 nm; and more preferably 30 to 200 nm.

[0024] In some of the literature, the term “exosome” also refers to protein complexes containing exoribonucleases which are involved in mRNA degradation and the processing of small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs) and ribosomal RNAs (rRNA) (Liu et al., 2006b; van Dijk et al., 2007). Such protein complexes do not have membranes and are not “microvesicles” or “exosomes” as those terms are used here in.

Exosomes As Diagnostic And/Or Prognostic Tools [0025] Certain aspects of the present invention are based on the surprising finding that glioblastoma derived micro vesicles can be isolated from the serum of glioblastoma patients. This is the first discovery of microvesicles derived from cells in the brain, present in a bodily fluid of a subject. Prior to this discovery it was not known whether glioblastoma cells produced microvesicles or whether such microvesicles could cross the blood brain barrier into the rest of the body. These microvesicles were found to contain mutant mRNA associated with tumor cells. The microvesicles also contained microRNAs (miRNAs) which

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2017272272 07 Dec 2017 were found to be abundant in glioblastomas. Glioblastoma-derived micro vesicles were also found to potently promote angiogenic features in primary human brain microvascular endothelial cells (HBMVEC) in culture. This angiogenic effect was mediated at least in part through angiogenic proteins present in the microvesicles. The nucleic acids found within these microvesicles, as well as other contents of the microvesicles such as angiogenic proteins, can be used as valuable biomarkers for tumor diagnosis, characterization and prognosis by providing a genetic profile. Contents within these microvesicles can also be used to monitor tumor progression over time by analyzing if other mutations are acquired during tumor progression as well as if the levels of certain mutations are becoming increased or decreased over time or over a course of treatment [0026] Certain aspects of the present invention are based on the finding that micro vesicles are secreted by tumor cells and circulating in bodily fluids. The number of micro vesicles increases as the tumor grows. The concentration of the micro vesicles in bodily fluids is proportional to the corresponding tumor load. The bigger the tumor load, the higher the concentration of micro vesicles in bodily fluids.

[0027] Certain aspects of the present invention are based on another surprising finding that most of the extracellular RNAs in bodily fluid of a subject are contained within micro vesicles and thus protected from degradation by ribonucleases. As shown in Example 3, more than 90% of extracellular RNA in total serum can be recovered in micro vesicles.

[0028] One aspect of the present invention relates to methods for detecting, diagnosing, monitoring, treating or evaluating a disease or other medical condition in a subject by determining the concentration of microvesicles in a biological sample. The determination may be performed using the biological sample without first isolating the microvesicles or by isolating the microvesicles first.

[0029] Another aspect of the present invention relates to methods for detecting, diagnosing, monitoring, treating or evaluating a disease or other medical condition in a subject comprising the steps of, isolating exosomes from a bodily fluid of a subject, and analyzing one or more nucleic acids contained within the exosomes. The nucleic acids are analyzed qualitatively and/or quantitatively, and the results are compared to results expected or obtained for one or more other subjects who have or do not have the disease or other medical condition. The presence of a difference in microvesicular nucleic acid content of the subject, as compared to that of one or more other individuals, can indicate the presence or

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2017272272 07 Dec 2017 absence of, the progression of (e.g., changes of tumor size and tumor malignancy), or the susceptibility to a disease or other medical condition in the subject.

[0030] Indeed, the isolation methods and techniques described herein provide the following heretofore unrealized advantages: 1) the opportunity to selectively analyze diseaseor tumor-specific nucleic acids, which may be realized by isolating disease- or tumor-specific microvesicles apart from other microvesicles within the fluid sample; 2) significantly higher yield of nucleic acid species with higher sequence integrity as compared to the yield/integrity obtained by extracting nucleic acids directly from the fluid sample; 3) scalability, e.g. to detect nucleic acids expressed at low levels, the sensitivity can be increased by pelleting more micro vesicles from a larger volume of serum; 4) purer nucleic acids in that protein and lipids, debris from dead cells, and other potential contaminants and PCR inhibitors are excluded from the microvesicle pellets before the nucleic acid extraction step; and 5) more choices in nucleic acid extraction methods as microvesicle pellets are of much smaller volume than that of the starting serum, making it possible to extract nucleic acids from these microvesicle pellets using small volume column filters.

[0031] The microvesicles are preferably isolated from a sample taken of a bodily fluid from a subject. As used herein, a “bodily fluid” refers to a sample of fluid isolated from anywhere in the body of the subject, preferably a peripheral location, including but not limited to, for example, blood, plasma, serum, urine, sputum, spinal fluid, pleural fluid, nipple aspirates, lymph fluid, fluid of the respiratory, intestinal, and genitourinary tracts, tear fluid, saliva, breast milk, fluid from the lymphatic system, semen, cerebrospinal fluid, intraorgan system fluid, ascitic fluid, tumor cyst fluid, amniotic fluid and combinations thereof.

[0032] The term “subject” is intended to include all animals shown to or expected to have micro vesicles. In particular embodiments, the subject is a mammal, a human or nonhuman primate, a dog, a cat, a horse, a cow, other farm animals, or a rodent (e.g. mice, rats, guinea pig. etc.). The term “subject” and “individual” are used interchangeably herein.

[0033] Methods of isolating microvesicles from a biological sample are known in the art. For example, a method of differential centrifugation is described in a paper by Raposo et al. (Raposo et al., 1996), and similar methods are detailed in the Examples section herein. Methods of anion exchange and/or gel permeation chromatography are described in US Patent Nos. 6,899,863 and 6,812,023. Methods of sucrose density gradients or organelle electrophoresis are described in U.S. Patent No. 7,198,923. A method of magnetic activated

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2017272272 07 Dec 2017 cell sorting (MACS) is described in (Taylor and Gercel-Taylor, 2008). A method of nanomembrane ultrafiltration concentrator is described in (Cheruvanky et al., 2007). Preferably, microvesicles can be identified and isolated from bodily fluid of a subject by a newly developed microchip technology that uses a unique microfluidic platform to efficiently and selectively separate tumor derived microvesicles. This technology, as described in a paper by Nagrath et al. (Nagrath et al., 2007), can be adapted to identify and separate microvesicles using similar principles of capture and separation as taught in the paper. Each of the foregoing references is incorporated by reference herein for its teaching of these methods.

[0034] In one embodiment, the microvesicles isolated from a bodily fluid are enriched for those originating from a specific cell type, for example, lung, pancreas, stomach, intestine, bladder, kidney, ovary, testis, skin, colorectal, breast, prostate, brain, esophagus, liver, placenta, fetus cells. Because the micro vesicles often carry surface molecules such as antigens from their donor cells, surface molecules may be used to identify, isolate and/or enrich for microvesicles from a specific donor cell type (Al-Nedawi et al., 2008; Taylor and Gercel-Taylor, 2008). In this way, microvesicles originating from distinct cell populations can be analyzed for their nucleic acid content. For example, tumor (malignant and nonmalignant) micro vesicles carry tumor-associated surface antigens and may be detected, isolated and/or enriched via these specific tumor-associated surface antigens. In one example, the surface antigen is epithelial-cell-adhesion-molecule (EpCAM), which is specific to microvesicles from carcinomas of lung, colorectal, breast, prostate, head and neck, and hepatic origin, but not of hematological cell origin (Balzar et al., 1999; Went et al., 2004). In another example, the surface antigen is CD24, which is a glycoprotein specific to urine microvesicles (Keller et al., 2007). In yet another example, the surface antigen is selected from a group of molecules CD70, carcinoembryonic antigen (CEA), EGFR, EGFRvIII and other variants, Fas ligand, TRAIL, tranferrin receptor, p38.5, p97 and HSP72. Additionally, tumor specific micro vesicles may be characterized by the lack of surface markers, such as CD80 and CD86.

[0035] The isolation of microvesicles from specific cell types can be accomplished, for example, by using antibodies, aptamers, aptamer analogs or molecularly imprinted polymers specific for a desired surface antigen. In one embodiment, the surface antigen is specific for a cancer type. In another embodiment, the surface antigen is specific for a cell type which is not necessarily cancerous. One example of a method of micro vesicle separation based on cell

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2017272272 07 Dec 2017 surface antigen is provided in U.S. Patent No. 7,198,923. As described in, e.g., U.S. Patent Nos. 5,840,867 and 5,582,981, WO/2003/050290 and a publication by Johnson et al.

(Johnson et al., 2008), aptamers and their analogs specifically bind surface molecules and can be used as a separation tool for retrieving cell type-specific microvesicles. Molecularly imprinted polymers also specifically recognize surface molecules as described in, e.g., US Patent Nos. 6,525,154, 7,332,553 and 7,384,589 and a publication by Bossi et al. (Bossi et al., 2007) and are a tool for retrieving and isolating cell type-specific micro vesicles. Each of the foregoing reference is incorporated herein for its teaching of these methods.

[0036] It may be beneficial or otherwise desirable to extract the nucleic acid from the exosomes prior to the analysis. Nucleic acid molecules can be isolated from a microvesicle using any number of procedures, which are well-known in the art, the particular isolation procedure chosen being appropriate for the particular biological sample. Examples of methods for extraction are provided in the Examples section herein. In some instances, with some techniques, it may also be possible to analyze the nucleic acid without extraction from the microvesicle.

[0037] In one embodiment, the extracted nucleic acids, including DNA and/or RNA, are analyzed directly without an amplification step. Direct analysis may be performed with different methods including, but not limited to, the nanostring technology. NanoString technology enables identification and quantification of individual target molecules in a biological sample by attaching a color coded fluorescent reporter to each target molecule.

This approach is similar to the concept of measuring inventory by scanning barcodes. Reporters can be made with hundreds or even thousands of different codes allowing for highly multiplexed analysis. The technology is described in a publication by Geiss et al. (Geiss et al., 2008) and is incorporated herein by reference for this teaching.

[0038] In another embodiment, it may be beneficial or otherwise desirable to amplify the nucleic acid of the microvesicle prior to analyzing it. Methods of nucleic acid amplification are commonly used and generally known in the art, many examples of which are described herein. If desired, the amplification can be performed such that it is quantitative. Quantitative amplification will allow quantitative determination of relative amounts of the various nucleic acids, to generate a profile as described below.

[0039] In one embodiment, the extracted nucleic acid is RNA. RNAs are then preferably reverse-transcribed into complementary DNAs before further amplification. Such

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2017272272 07 Dec 2017 reverse transcription may be performed alone or in combination with an amplification step. One example of a method combining reverse transcription and amplification steps is reverse transcription polymerase chain reaction (RT-PCR), which may be further modified to be quantitative, e.g., quantitative RT-PCR as described in US Patent No. 5,639,606, which is incorporated herein by reference for this teaching.

[0040] Nucleic acid amplification methods include, without limitation, polymerase chain reaction (PCR) (US Patent No. 5,219,727) and its variants such as in situ polymerase chain reaction (US Patent No. 5,538,871), quantitative polymerase chain reaction (US Patent No. 5,219,727), nested polymerase chain reaction (US Patent No. 5,556,773), self sustained sequence replication and its variants (Guatelli et al., 1990), transcriptional amplification system and its variants (Kwoh et al., 1989), Qb Replicase and its variants (Miele et al., 1983), cold-PCR (Li et al., 2008) or any other nucleic acid amplification methods, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. Especially useful are those detection schemes designed for the detection of nucleic acid molecules if such molecules are present in very low numbers. The foregoing references are incorporated herein for their teachings of these methods.

[0041] The analysis of nucleic acids present in the microvesicles is quantitative and/or qualitative. For quantitative analysis, the amounts (expression levels), either relative or absolute, of specific nucleic acids of interest within the microvesicles are measured with methods known in the art (described below). For qualitative analysis, the species of specific nucleic acids of interest within the microvesicles, whether wild type or variants, are identified with methods known in the art (described below).

[0042] “Genetic aberrations” is used herein to refer to the nucleic acid amounts as well as nucleic acid variants within the micro vesicles. Specifically, genetic aberrations include, without limitation, over-expression of a gene (e.g., oncogenes) or a panel of genes, underexpression of a gene (e.g., tumor suppressor genes such as p53 or RB) or a panel of genes, alternative production of splice variants of a gene or a panel of genes, gene copy number variants (CNV) (e.g. DNA double minutes) (Hahn, 1993), nucleic acid modifications (e.g., methylation, acetylation and phosphorylations), single nucleotide polymorphisms (SNPs), chromosomal rearrangements (e.g., inversions, deletions and duplications), and mutations (insertions, deletions, duplications, missense, nonsense, synonymous or any other nucleotide changes) of a gene or a panel of genes, which mutations, in many cases, ultimately affect the

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2017272272 07 Dec 2017 activity and function of the gene products, lead to alternative transcriptional splicing variants and/or changes of gene expression level.

[0043] The determination of such genetic aberrations can be performed by a variety of techniques known to the skilled practitioner. For example, expression levels of nucleic acids, alternative splicing variants, chromosome rearrangement and gene copy numbers can be determined by microarray analysis (US Patent Nos. 6,913,879, 7,364,848, 7,378,245, 6,893,837 and 6,004,755) and quantitative PCR. Particularly, copy number changes may be detected with the Illumina Infinium II whole genome genotyping assay or Agilent Human Genome CGH Microarray (Steemers et al., 2006). Nucleic acid modifications can be assayed by methods described in, e.g., US Patent No. 7,186,512 and patent publication

WO/2003/023065. Particularly, methylation profiles may be determined by Illumina DNA Methylation OMA003 Cancer Panel. SNPs and mutations can be detected by hybridization with allele-specific probes, enzymatic mutation detection, chemical cleavage of mismatched heteroduplex (Cotton et al., 1988), ribonuclease cleavage of mismatched bases (Myers et al., 1985), mass spectrometry (US Patent Nos. 6,994,960, 7,074,563, and 7,198,893), nucleic acid sequencing, single strand conformation polymorphism (SSCP) (Orita et al., 1989), denaturing gradient gel electrophoresis (DGGE)(Fischer and Lerman, 1979a; Fischer and Lerman, 1979b), temperature gradient gel electrophoresis (TGGE) (Fischer and Lerman, 1979a; Fischer and Lerman, 1979b), restriction fragment length polymorphisms (RFLP) (Kan and Dozy, 1978a; Kan and Dozy, 1978b), oligonucleotide ligation assay (OLA), allele-specific PCR (ASPCR) (US Patent No. 5,639,611), ligation chain reaction (LCR) and its variants (Abravaya et al., 1995; Landegren et al., 1988; Nakazawa et al., 1994), flow-cytometric heteroduplex analysis (WO/2006/113590) and combinations/modifications thereof. Notably, gene expression levels may be determined by the serial analysis of gene expression (SAGE) technique (Velculescu et al., 1995). In general, the methods for analyzing genetic aberrations are reported in numerous publications, not limited to those cited herein, and are available to skilled practitioners. The appropriate method of analysis will depend upon the specific goals of the analysis, the condition/history of the patient, and the specific cancer(s), diseases or other medical conditions to be detected, monitored or treated. The forgoing references are incorporated herein for their teachings of these methods.

[0044] A variety of genetic aberrations have been identified to occur and/or contribute to the initial generation or progression of cancer. Examples of genes which are commonly up-regulated (i.e. over-expressed) in cancer are provided in Table 4 (cancers of different

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2017272272 07 Dec 2017 types) and Table 6 (pancreatic cancer). Examples of microRNAs which are up-regulated in brain tumor are provided in Table 8. In one embodiment of the invention, there is an increase in the nucleic acid expression level of a gene listed in Table 4 and/or Table 6 and/or of a microRNA listed in Table 8. Examples of genes which are commonly down-regulated (e.g. under-expressed) in cancer are provided in Table 5 (cancers of different types) and Table 7 (pancreatic cancer). Examples of microRNAs which are down-regulated in brain tumor are provided in Table 9. In one embodiment of the invention, there is a decrease in the nucleic acid expression level of a gene listed in Table 5 and/or Table 7 and/or a microRNA listed in Table 9. Examples of genes which are commonly under expressed, or over expressed in brain tumors are reviewed in (Furnari et al., 2007) , and this subject matter is incorporated herein by reference. With respect to the development of brain tumors, RB and p53 are often down-regulated to otherwise decrease their tumor suppressive activity. Therefore, in these embodiments, the presence or absence of an increase or decrease in the nucleic acid expression level of a gene(s) and/or a microRNA(s) whose disregulated expression level is specific to a type of cancer can be used to indicate the presence or absence of the type of cancer in the subject.

[0045] Likewise, nucleic acid variants, e.g., DNA or RNA modifications, single nucleotide polymorphisms (SNPs) and mutations (e.g., missense, nonsense, insertions, deletions, duplications) may also be analyzed within microvesicles from bodily fluid of a subject, including pregnant females where microvesicles derived from the fetus may be in serum as well as amniotic fluid. Non-limiting examples are provided in Table 3. In yet a further embodiment, the nucleotide variant is in the EGFR gene. In a still further embodiment, the nucleotide variant is the EGFRvIII mutation/variant. The terms “EGFR”,“epidermal growth factor receptor” and “ErbBl”are used interchangeably in the art, for example as described in a paper by Carpenter (Carpenter, 1987). With respect to the development of brain tumors, RB, PTEN, pl6, p21 and p53 are often mutated to otherwise decrease their tumor suppressive activity. Examples of specific mutations in specific forms of brain tumors are discussed in a paper by Furnari et al. (Furnari et al., 2007), and this subject matter is incorporated herein by reference.

[0046] In addition, more genetic aberrations associated with cancers have been identified recently in a few ongoing research projects. For example, the Cancer Genome Atlas (TCGA) program is exploring a spectrum of genomic changes involved in human cancers. The results of this project and other similar research efforts are published and

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2017272272 07 Dec 2017 incorporated herein by reference (Jones et al., 2008; McLendon et al., 2008; Parsons et al., 2008; Wood et al., 2007). Specifically, these research projects have identified genetic aberrations, such as mutations (e.g., missense, nonsense, insertions, deletions and duplications), gene expression level variations (mRNA or microRNA), copy number variations and nucleic acid modification (e.g. methylation), in human glioblastoma, pancreatic cancer, breast cancer and/or colorectal cancer. The genes most frequently mutated in these cancers are listed in Table 11 and Table 12 (glioblastoma), Table 13 (pancreatic cancer), Table 14 (breast cancer) and Table 15 (colorectal cancer). The genetic aberrations in these genes, and in fact any genes which contain any genetic aberrations in a cancer, are targets that may be selected for use in diagnosing and/or monitoring cancer by the methods described herein.

[0047] Detection of one or more nucleotide variants can be accomplished by performing a nucleotide variant screen on the nucleic acids within the micro vesicles. Such a screen can be as wide or narrow as determined necessary or desirable by the skilled practitioner. It can be a wide screen (set up to detect all possible nucleotide variants in genes known to be associated with one or more cancers or disease states). Where one specific cancer or disease is suspected or known to exist, the screen can be specific to that cancer or disease. One example is a brain tumor/brain cancer screen (e.g., set up to detect all possible nucleotide variants in genes associated with various clinically distinct subtypes of brain cancer or known drug-resistant or drug-sensitive mutations of that cancer).

[0048] In one embodiment, the analysis is of a profile of the amounts (levels) of specific nucleic acids present in the microvesicle, herein referred to as a “quantitative nucleic acid profile” of the micro vesicles. In another embodiment, the analysis is of a profile of the species of specific nucleic acids present in the microvesicles (both wild type as well as variants), herein referred to as a “nucleic acid species profile.” A term used herein to refer to a combination of these types of profiles is “genetic profile” which refers to the determination of the presence or absence of nucleotide species, variants and also increases or decreases in nucleic acid levels.

[0049] Once generated, these genetic profiles of the microvesicles are compared to those expected in, or otherwise derived from a healthy normal individual. A profile can be a genome wide profile (set up to detect all possible expressed genes or DNA sequences). It can be narrower as well, such as a cancer wide profile (set up to detect all possible genes or nucleic acids derived therefrom, or known to be associated with one or more cancers).

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Where one specific cancer is suspected or known to exist, the profile can be specific to that cancer (e.g., set up to detect all possible genes or nucleic acids derived therefrom, associated with various clinically distinct subtypes of that cancer or known drug-resistant or sensitive mutations of that cancer).

[0050] Which nucleic acids are to be amplified and/or analyzed can be selected by the skilled practitioner. The entire nucleic acid content of the exosomes or only a subset of specific nucleic acids which are likely or suspected of being influenced by the presence of a disease or other medical condition such as cancer, can be amplified and/or analyzed. The identification of a nucleic acid aberration(s) in the analyzed microvesicle nucleic acid can be used to diagnose the subject for the presence of a disease such as cancer, hereditary diseases or viral infection with which that aberration(s) is associated. For instance, analysis for the presence or absence of one or more nucleic acid variants of a gene specific to a cancer (e.g. the EGFRvIII mutation) can indicate the cancer’s presence in the individual. Alternatively, or in addition, analysis of nucleic acids for an increase or decrease in nucleic acid levels specific to a cancer can indicate the presence of the cancer in the individual (e.g., a relative increase in EGFR nucleic acid, or a relative decrease in a tumor suppressor gene such as _P53).

[0051] In one embodiment, mutations of a gene which is associated with a disease such as cancer (e.g. via nucleotide variants, over-expression or under-expression) are detected by analysis of nucleic acids in micro vesicles, which nucleic acids are derived from the genome itself in the cell of origin or exogenous genes introduced through viruses. The nucleic acid sequences may be complete or partial, as both are expected to yield useful information in diagnosis and prognosis of a disease. The sequences may be sense or anti-sense to the actual gene or transcribed sequences. The skilled practitioner will be able to devise detection methods for a nucleotide variance from either the sense or anti-sense nucleic acids which may be present in a microvesicle. Many such methods involve the use of probes which are specific for the nucleotide sequences which directly flank, or contain the nucleotide variances. Such probes can be designed by the skilled practitioner given the knowledge of the gene sequences and the location of the nucleic acid variants within the gene. Such probes can be used to isolate, amplify, and/or actually hybridize to detect the nucleic acid variants, as described in the art and herein.

[0052] Determining the presence or absence of a particular nucleotide variant or plurality of variants in the nucleic acid within microvesicles from a subject can be performed

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2017272272 07 Dec 2017 in a variety of ways. A variety of methods are available for such analysis, including, but not limited to, PCR, hybridization with allele-specific probes, enzymatic mutation detection, chemical cleavage of mismatches, mass spectrometry or DNA sequencing, including minisequencing. In particular embodiments, hybridization with allele specific probes can be conducted in two formats: 1) allele specific oligonucleotides bound to a solid phase (glass, silicon, nylon membranes) and the labeled sample in solution, as in many DNA chip applications, or 2) bound sample (often cloned DNA or PCR amplified DNA) and labeled oligonucleotides in solution (either allele specific or short so as to allow sequencing by hybridization). Diagnostic tests may involve a panel of variances, often on a solid support, which enables the simultaneous determination of more than one variance. In another embodiment, determining the presence of at least one nucleic acid variance in the microvesicle nucleic acid entails a haplotyping test. Methods of determining haplotypes are known to those of skill in the art, as for example, in WO 00/04194.

[0053] In one embodiment, the determination of the presence or absence of a nucleic acid variant(s) involves determining the sequence of the variant site or sites (the exact location within the sequence where the nucleic acid variation from the norm occurs) by methods such as polymerase chain reaction (PCR), chain terminating DNA sequencing (US Patent No. 5547859), minisequencing (Fiorentino et al., 2003), oligonucleotide hybridization, pyrosequencing, Ulumina genome analyzer, deep sequencing, mass spectrometry or other nucleic acid sequence detection methods. Methods for detecting nucleic acid variants are well known in the art and disclosed in WO 00/04194, incorporated herein by reference. In an exemplary method, the diagnostic test comprises amplifying a segment of DNA or RNA (generally after converting the RNA to complementary DNA) spanning one or more known variants in the desired gene sequence. This amplified segment is then sequenced and/or subjected to electrophoresis in order to identify nucleotide variants in the amplified segment.

[0054] In one embodiment, the invention provides a method of screening for nucleotide variants in the nucleic acid of microvesicles isolated as described herein. This can be achieved, for example, by PCR or, alternatively, in a ligation chain reaction (LCR) (Abravaya et al., 1995; Landegren et al., 1988; Nakazawa et al., 1994). LCR can be particularly useful for detecting point mutations in a gene of interest (Abravaya et al., 1995). The LCR method comprises the steps of designing degenerate primers for amplifying the target sequence, the primers corresponding to one or more conserved regions of the nucleic acid corresponding to the gene of interest, amplifying PCR products with the primers using, as a template, a nucleic

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2017272272 07 Dec 2017 acid obtained from a micro vesicle, and analyzing the PCR products. Comparison of the PCR products of the microvesicle nucleic acid to a control sample (either having the nucleotide variant or not) indicates variants in the microvesicle nucleic acid. The change can be either an absence or presence of a nucleotide variant in the microvesicle nucleic acid, depending upon the control.

[0055] Analysis of amplification products can be performed using any method capable of separating the amplification products according to their size, including automated and manual gel electrophoresis, mass spectrometry, and the like.

[0056] Alternatively, the amplification products can be analyzed based on sequence differences, using SSCP, DGGE, TGGE, chemical cleavage, OLA, restriction fragment length polymorphisms as well as hybridization, for example, nucleic acid microarrays.

[0057] The methods of nucleic acid isolation, amplification and analysis are routine for one skilled in the art and examples of protocols can be found, for example, in Molecular Cloning: A Laboratory Manual (3-Volume Set) Ed. Joseph Sambrook, David W. Russel, and Joe Sambrook, Cold Spring Harbor Laboratory, 3rd edition (January 15, 2001), ISBN: 0879695773. A particular useful protocol source for methods used in PCR amplification is PCR Basics: From Background to Bench by Springer Verlag; 1st edition (October 15, 2000), ISBN: 0387916008.

[0058] Many methods of diagnosis performed on a tumor biopsy sample can be performed with micro vesicles since tumor cells, as well as some normal cells are known to shed microvesicles into bodily fluid and the genetic aberrations within these microvesicles reflect those within tumor cells as demonstrated herein. Furthermore, methods of diagnosis using microvesicles have characteristics that are absent in methods of diagnosis performed directly on a tumor biopsy sample. For example, one particular advantage of the analysis of microvesicular nucleic acids, as opposed to other forms of sampling of tumor/cancer nucleic acid, is the availability for analysis of tumor/cancer nucleic acids derived from all foci of a tumor or genetically heterogeneous tumors present in an individual. Biopsy samples are limited in that they provide information only about the specific focus of the tumor from which the biopsy is obtained. Different tumorous/cancerous foci found within the body, or even within a single tumor often have different genetic profiles and are not analyzed in a standard biopsy. However, analysis of the microvesicular nucleic acids from an individual presumably provides a sampling of all foci within an individual. This provides valuable

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2017272272 07 Dec 2017 information with respect to recommended treatments, treatment effectiveness, disease prognosis, and analysis of disease recurrence, which cannot be provided by a simple biopsy.

[0059] Identification of genetic aberrations associated with specific diseases and/or medical conditions by the methods described herein can also be used for prognosis and treatment decisions of an individual diagnosed with a disease or other medical condition such as cancer. Identification of the genetic basis of a disease and/or medical condition provides useful information guiding the treatment of the disease and/or medical condition. For example, many forms of chemotherapy have been shown to be more effective on cancers with specific genetic abnormalities/aberrations. One example is the effectiveness of EGFRtargeting treatments with medicines, such as the kinase inhibitors gefitinib and erlotinib.

Such treatment have been shown to be more effective on cancer cells whose EGFR gene harbors specific nucleotide mutations in the kinase domain of EGFR protein (U.S. Patent publication 20060147959). In other words, the presence of at least one of the identified nucleotide variants in the kinase domain of EGFR nucleic acid message indicates that a patient will likely benefit from treatment with the EGFR-targeting compound gefitinib or erlotinib. Such nucleotide variants can be identified in nucleic acids present in micro vesicles by the methods described herein, as it has been demonstrated that EGFR transcripts of tumor origin are isolated from microvesicles in bodily fluid.

[0060] Genetic aberrations in other genes have also been found to influence the effectiveness of treatments. As disclosed in the publication by Furnari et al. (Furnari et al., 2007), mutations in a variety of genes affect the effectiveness of specific medicines used in chemotherapy for treating brain tumors. The identification of these genetic aberrations in the nucleic acids within micro vesicles will guide the selection of proper treatment plans.

[0061] As such, aspects of the present invention relate to a method for monitoring disease (e.g. cancer) progression in a subject, and also to a method for monitoring disease recurrence in an individual. These methods comprise the steps of isolating microvesicles from a bodily fluid of an individual, as discussed herein, and analyzing nucleic acid within the microvesicles as discussed herein (e.g. to create a genetic profile of the microvesicles). The presence/absence of a certain genetic aberration/profile is used to indicate the presence/absence of the disease (e.g. cancer) in the subject as discussed herein. The process is performed periodically over time, and the results reviewed, to monitor the progression or regression of the disease, or to determine recurrence of the disease. Put another way, a change in the genetic profile indicates a change in the disease state in the subject. The period

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2017272272 07 Dec 2017 of time to elapse between sampling of microvesicles from the subject, for performance of the isolation and analysis of the microvesicle, will depend upon the circumstances of the subject, and is to be determined by the skilled practitioner. Such a method would prove extremely beneficial when analyzing a nucleic acid from a gene that is associated with the therapy undergone by the subject. For example, a gene which is targeted by the therapy can be monitored for the development of mutations which make it resistant to the therapy, upon which time the therapy can be modified accordingly. The monitored gene may also be one which indicates specific responsiveness to a specific therapy.

[0062] Aspects of the present invention also relate to the fact that a variety of noncancer diseases and/or medical conditions also have genetic links and/or causes, and such diseases and/or medical conditions can likewise be diagnosed and/or monitored by the methods described herein. Many such diseases are metabolic, infectious or degenerative in nature. One such disease is diabetes (e.g. diabetes insipidus) in which the vasopressin type 2 receptor (V2R) is modified. Another such disease is kidney fibrosis in which the genetic profiles for the genes of collagens, fibronectin and TGF-β are changed. Changes in the genetic profile due to substance abuse (e.g. a steroid or drug use), viral and/or bacterial infection, and hereditary disease states can likewise be detected by the methods described herein.

[0063] Diseases or other medical conditions for which the inventions described herein are applicable include, but are not limited to, nephropathy, diabetes insipidus, diabetes type I, diabetes II, renal disease glomerulonephritis, bacterial or viral glomerulonephritides, IgA nephropathy, Henoch-Schonlein Purpura, membranoproliferative glomerulonephritis, membranous nephropathy, Sjogren's syndrome, nephrotic syndrome minimal change disease, focal glomerulosclerosis and related disorders, acute renal failure, acute tubulointerstitial nephritis, pyelonephritis, GU tract inflammatory disease, Pre-clampsia, renal graft rejection, leprosy, reflux nephropathy, nephrolithiasis, genetic renal disease, medullary cystic, medullar sponge, polycystic kidney disease, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, tuberous sclerosis, von Hippel-Lindau disease, familial thin-glomerular basement membrane disease, collagen III glomerulopathy, fibronectin glomerulopathy, Alport's syndrome, Fabry's disease, Nail-Patella Syndrome, congenital urologic anomalies, monoclonal gammopathies, multiple myeloma, amyloidosis and related disorders, febrile illness, familial Mediterranean fever, HIV infection-AIDS, inflammatory disease, systemic vasculitides, polyarteritis nodosa, Wegener's granulomatosis, polyarteritis,

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2017272272 07 Dec 2017 necrotizing and crecentic glomerulonephritis, polymyositis-dermatomyositis, pancreatitis, rheumatoid arthritis, systemic lupus erythematosus, gout, blood disorders, sickle cell disease, thrombotic thrombocytopenia purpura, Fanconi’s syndrome, transplantation, acute kidney injury, irritable bowel syndrome, hemolytic-uremic syndrome, acute corticol necrosis, renal thromboembolism, trauma and surgery, extensive injury, bums, abdominal and vascular surgery, induction of anesthesia, side effect of use of drugs or drug abuse, circulatory disease myocardial infarction, cardiac failure, peripheral vascular disease, hypertension, coronary heart disease, non-atherosclerotic cardiovascular disease, atherosclerotic cardiovascular disease, skin disease, soriasis, systemic sclerosis, respiratory disease, COPD, obstructive sleep apnoea, hypoia at high altitude or erdocrine disease, acromegaly, diabetes mellitus, or diabetes insipidus.

[0064] Selection of an individual from whom the microvesicles are isolated is performed by the skilled practitioner based upon analysis of one or more of a variety of factors. Such factors for consideration are whether the subject has a family history of a specific disease (e.g. a cancer), has a genetic predisposition for such a disease, has an increased risk for such a disease due to family history, genetic predisposition, other disease or physical symptoms which indicate a predisposition, or environmental reasons. Environmental reasons include lifestyle, exposure to agents which cause or contribute to the disease such as in the air, land, water or diet. In addition, having previously had the disease, being currently diagnosed with the disease prior to therapy or after therapy, being currently treated for the disease (undergoing therapy), being in remission or recovery from the disease, are other reasons to select an individual for performing the methods.

[0065] The methods described herein are optionally performed with the additional step of selecting a gene or nucleic acid for analysis, prior to the analysis step. This selection can be based on any predispositions of the subject, or any previous exposures or diagnosis, or therapeutic treatments experienced or concurrently undergone by the subject.

[0066] The cancer diagnosed, monitored or otherwise profiled, can be any kind of cancer. This includes, without limitation, epithelial cell cancers such as lung, ovarian, cervical, endometrial, breast, brain, colon and prostate cancers. Also included are gastrointestinal cancer, head and neck cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer, melanoma, and leukemia. In addition, the methods and compositions of the present invention are equally applicable to detection, diagnosis and

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2017272272 07 Dec 2017 prognosis of non-malignant tumors in an individual (e.g. neurofibromas, meningiomas and schwannomas).

[0067] In one embodiment, the cancer is brain cancer. Types of brain tumors and cancer are well known in the art. Glioma is a general name for tumors that arise from the glial (supportive) tissue of the brain. Gliomas are the most common primary brain tumors. Astrocytomas, ependymomas, oligodendrogliomas, and tumors with mixtures of two or more cell types, called mixed gliomas, are the most common gliomas. The following are other common types of brain tumors: Acoustic Neuroma (Neurilemmoma, Schwannoma. Neurinoma), Adenoma, Astracytoma, Low-Grade Astrocytoma, giant cell astrocytomas, Midand High-Grade Astrocytoma, Recurrent tumors, Brain Stem Glioma, Chordoma, Choroid Plexus Papilloma, CNS Lymphoma (Primary Malignant Lymphoma), Cysts, Dermoid cysts, Epidermoid cysts, Craniopharyngioma, Ependymoma Anaplastic ependymoma, Gangliocytoma (Ganglioneuroma), Ganglioglioma, Glioblastoma Multiforme (GBM), Malignant Astracytoma, Glioma, Hemangioblastoma, Inoperable Brain Tumors, Lymphoma, Medulloblastoma (MDL), Meningioma, Metastatic Brain Tumors, Mixed Glioma, Neurofibromatosis, Oligodendroglioma. Optic Nerve Glioma, Pineal Region Tumors, Pituitary Adenoma, PNET (Primitive Neuroectodermal Tumor), Spinal Tumors, Subependymoma, and Tuberous Sclerosis (Bourneville’s Disease).

[0068] In addition to identifying previously known nucleic acid aberrations (as associated with diseases), the methods of the present invention can be used to identify previously unidentified nucleic acid sequences/modifications (e.g. post transcriptional modifications) whose aberrations are associated with a certain disease and/or medical condition. This is accomplished, for example, by analysis of the nucleic acid within microvesicles from a bodily fluid of one or more subjects with a given disease/medical condition (e.g. a clinical type or subtype of cancer) and comparison to the nucleic acid within microvesicles of one or more subjects without the given disease/medical condition, to identify differences in their nucleic acid content. The differences may be any genetic aberrations including, without limitation, expression level of the nucleic acid, alternative splice variants, gene copy number variants (CNV), modifications of the nucleic acid , single nucleotide polymorphisms (SNPs), and mutations (insertions, deletions or single nucleotide changes) of the nucleic acid. Once a difference in a genetic parameter of a particular nucleic acid is identified for a certain disease, further studies involving a clinically and statistically significant number of subjects may be carried out to establish the correlation between the

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2017272272 07 Dec 2017 genetic aberration of the particular nucleic acid and the disease. The analysis of genetic aberrations can be done by one or more methods described herein, as determined appropriate by the skilled practitioner.

Exosomes As Delivery Vehicles [0069] Aspects of the present invention also relate to the actual microvesicles described herein. In one embodiment, the invention is an isolated microvesicle as described herein, isolated from an individual. In one embodiment, the microvesicle is produced by a cell within the brain of the individual (e.g. a tumor or non-tumor cell). In another embodiment, the microvesicle is isolated from a bodily fluid of an individual, as described herein.

Methods of isolation are described herein.

[0070] Another aspect of the invention relates to the finding that isolated microvesicles from human glioblastoma cells contain mRNAs, miRNAs and angiogenic proteins. Such glioblastoma microvesicles were taken up by primary human brain endothelial cells, likely via an endocytotic mechanism, and a reporter protein mRNA incorporated into the microvesicles was translated in those cells. This indicates that messages delivered by microvesicles can change the genetic and/or translational profile of a target cell (a cell which takes up a microvesicle). The micro vesicles also contained miRNAs which are known to be abundant in glioblastomas (Krichevsky et al, manuscript in preparation). Thus micro vesicles derived from glioblastoma tumors function as delivery vehicles for mRNA, miRNA and proteins which can change the translational state of other cells via delivery of specific mRNA species, promote angiogenesis of endothelial cells, and stimulate tumor growth.

[0071] In one embodiment, microvesicles are depleted from a bodily fluid from a donor subject before said bodily fluid is delivered to a recipient subject. The donor subject may be a subject with an undetectable tumor and the microvesicles in the bodily fluid are derived from the tumor. The tumor microvesicles in the donor bodily fluid, if unremoved, would be harmful since the genetic materials and proteins in the microvesicle may promote unrestricted growth of cells in the recipient subject.

[0072] As such, another aspect of the invention is the use of the microvesicles identified herein to deliver a nucleic acid to a cell. In one embodiment, the cell is within the body of an individual. The method comprises administering a microvesicle(s) which contains the nucleic acid, or a cell that produces such micro vesicles, to the individual such that the

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2017272272 07 Dec 2017 microvesicles contacts and/or enters the cell of the individual. The cell to which the nucleic acid gets delivered is referred to as the target cell.

[0073] The microvesicle can be engineered to contain a nucleic acid that it would not naturally contain (i.e. which is exogenous to the normal content of the micro vesicle). This can be accomplished by physically inserting the nucleic acid into the micro vesicles. Alternatively, a cell (e.g. grown in culture) can be engineered to target one or more specific nucleic acid into the exosome, and the exosome can be isolated from the cell. Alternatively, the engineered cell itself can be administered to the individual.

[0074] In one embodiment, the cell which produces the exosome for administration is of the same or similar origin or location in the body as the target cell. That is to say, for delivery of a microvesicle to a brain cell, the cell which produces the microvesicle would be a brain cell (e.g. a primary cell grown in culture). In another embodiment, the cell which produces the exosome is of a different cell type than the target cell. In one embodiment, the cell which produces the exosome is a type that is located proximally in the body to the target cell.

[0075] A nucleic acid sequence which can be delivered to a cell via an exosome can be RNA or DNA, and can be single or double stranded, and can be selected from a group comprising: nucleic acid encoding a protein of interest, oligonucleotides, nucleic acid analogues, for example peptide-nucleic acid (PNA), pseudo-complementary PNA (pc-PNA), locked nucleic acid (LNA) etc. Such nucleic acid sequences include, for example, but are not limited to, nucleic acid sequences encoding proteins, for example that act as transcriptional repressors, antisense molecules, ribozymes, small inhibitory nucleic acid sequences, for example but are not limited to RNAi, shRNA, siRNA, miRNA, antisense oligonucleotides, and combinations thereof.

[0076] Microvesicles isolated from a cell type are delivered to a recipient subject. Said microvesicles may benefit the recipient subject medically. For example, the angiogenesis and pro-proliferation effects of tumor exosomes may help the regeneration of injured tissues in the recipient subject. In one embodiment, the delivery means is by bodily fluid transfusion wherein microvesicles are added into a bodily fluid from a donor subject before said bodily fluid is delivered to a recipient subject.

[0077] In another embodiment, the microvesicle is an ingredient (e.g. the active ingredient in a pharmaceutically acceptable formulation suitable for administration to the

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2017272272 07 Dec 2017 subject (e.g. in the methods described herein). Generally this comprises a pharmaceutically acceptable carrier for the active ingredient. The specific carrier will depend upon a number of factors (e.g.. the route of administration).

[0078] The “pharmaceutically acceptable carrier” means any pharmaceutically acceptable means to mix and/or deliver the targeted delivery composition to a subject. This includes a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and is compatible with administration to a subject, for example a human.

[0079] Administration to the subject can be either systemic or localized. This includes, without limitation, dispensing, delivering or applying an active compound (e.g. in a pharmaceutical formulation) to the subject by any suitable route for delivery of the active compound to the desired location in the subject, including delivery by either the parenteral or oral route, intramuscular injection, subcutaneous/intradermal injection, intravenous injection, buccal administration, transdermal delivery and administration by the rectal, colonic, vaginal, intranasal or respiratory tract route.

[0080] It should be understood that this invention is not limited to the particular methodologies, protocols and reagents, described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0081] In one respect, the present invention relates to the herein described compositions, methods, and respective components thereof, as essential to the invention, yet open to the inclusion of unspecified elements, essential or not (“comprising”). In some embodiments, other elements to be included in the description of the composition, method or respective component thereof are limited to those that do not materially affect the basic and novel characteristic(s) of the invention (“consisting essentially of’). This applies equally to steps within a described method as well as compositions and components therein. In other embodiments, the inventions, compositions, methods, and respective components thereof, described herein are intended to be exclusive of any element not deemed an essential element to the component, composition or method (“consisting of’).

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EXAMPLES

Examples 1-7. Tumor cells shed microvesicles, which contain RNAs, including mRNAs and microRNAs, and that microvesicles contain more than 90% of the extracellular RNA in bodily fluids.

Example 1: Micro vesicles are shed from primary human glioblastoma cells.

[0082] Glioblastoma tissue was obtained from surgical resections and tumor cells were dissociated and cultured as monolayers. Specifically, brain tumor specimens from patients diagnosed by a neuropathologist as glioblastoma multiforme were taken directly from surgery and placed in cold sterile Neurobasal media (Invitrogen, Carlsbad, CA, USA). The specimens were dissociated into single cells within 1 hr from the time of surgery using a Neural Tissue Dissociation Kit (Miltenyi Biotech, Berisch Gladbach, Germany) and plated in DMEM 5% dFBS supplemented with penicillin-streptomycin (10 IU ml¹ and 10 pg ml¹, respectively, Sigma-Aldrich, St Louis, MO, USA). Because microvesicles can be found in the fetal bovine serum (FBS) traditionally used to cultivate cells, and these microvesicles contain substantial amounts of mRNA and miRNA, it was important to grow the tumor cells in media containing microvesicle-depleted FBS (dFBS). Cultured primary cells obtained from three glioblastoma tumors were found to produce microvesicles at both early and later passages (a passage is a cellular generation defined by the splitting of cells, which is a common cell culture technique and is necessary to keep the cells alive). The microvesicles were able to be detected by scanning electronmicroscopy (FIGS la and lb) and transmission electronmicroscopy (FIG If)· Briefly, human glioblastoma cells were placed on ornithinecoated cover-slips, fixed in 0.5x Karnovskys fixative and then washed 2x5min (2 times with 5 min each) with PBS. The cells were dehydrated in 35% EtOH 10 min, 50% EtOH 2x 10 min, 70% EtOH 2x 10 min, 95% EtOH 2x 10 min, and 100% EtOH 4 x 10 min. The cells were then transferred to critical point drying in a Tousimis SAMDR1-795 semi-automatic Critical Point Dryer followed by coating with chromium in a GAT AN Model 681 High Resolution Ion Beam Coater. As shown in FIGS, la and lb, tumor cells were covered with microvesicles varying in size from about 50 - 500 nm.

Example 2: Glioblastoma microvesicles contain RNA.

[0083] To isolate microvesicles, glioblastoma cells at passage 1-15 were cultured in microvesicle-free media (DMEM containing 5% dFBS prepared by ultracentrifugation at 110,000 x g for 16 hours to remove bovine microvesicles). The conditioned medium from 40

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2017272272 07 Dec 2017 million cells was harvested after 48 hours. The micro vesicles were purified by differential centrifugation. Specifically, glioblastoma conditioned medium was centrifuged for 10 min at 300 x g to eliminate any cell contamination. Supernatants were further centrifuged for 20 min at 16,500 x g and filtered through a 0.22 pm filter. Microvesicles were then pelleted by ultracentrifugation at 110,000 x g for 70 min. The microvesicle pellets were washed in 13 ml PBS, pelleted again and resuspended in PBS.

[0084] Isolated microvesicles were measured for their total protein content using DC Protein Assay (Bio-Rad, Hercules, CA, USA).

[0085] For the extraction of RNA from micro vesicles, RNase A (Fermentas, Glen Bumie, MD, USA) at a final concentration of 100 pg/ml was added to suspensions of micro vesicles and incubated for 15 min at 37 °C to get rid of RNA outside of the microvesicles and thus ensure that the extracted RNA would come from inside the micro vesicles. Total RNA was then extracted from the microvesicles using the MirVana RNA isolation kit (Ambion, Austin TX, USA) according to the manufacturer’s protocol.

After treatment with DNAse according to the manufacturer’s protocol, the total RNA was quantified using a nanodrop ND-1000 instrument (Thermo Fischer Scientific, Wilmington, DE, USA).

[0086] Glioblastoma microvesicles were found to contain RNA and protein in a ratio of approximately 1:80 (pg RNA:pg protein). The average yield of proteins and RNAs isolated from microvesicles over a 48-hour period in culture was around 4 pg protein and 50 ng RNA/million cells.

[0087] To confirm that the RNA was contained inside the microvesicles, microvesicles were either exposed to RNase A or mock treatment before RNA extraction (FIG. lc). There was never more than a 7% decrease in RNA content following RNase treatment. Thus, it appears that almost all of the extracellular RNA from the media is contained within the microvesicles and is thereby protected from external RNases by the surrounding vesicular membrane.

[0088] Total RNA from microvesicles and their donor cells were analyzed with a Bioanalyzer, showing that the microvesicles contain a broad range of RNA sizes consistent with a variety of mRNAs and miRNAs, but lack 18S and 28S the ribosomal RNA peaks characteristic of cellular RNA (FIGS. Id and le).

Example 3: Microvesicles contain DNA.

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2017272272 07 Dec 2017 [0089] To test if microvesicles also contain DNA, exosomes were isolated as mentioned in Example 2 and then treated with DNase before being lysed to release contents. The DNase treatment step was to remove DNA outside of the exosomes so that only DNA residing inside the exosomes was extracted. Specifically, the DNase treatment was performed using the DNA-free kit from Ambion according to manufacturer’s recommendations (Catalog#AM1906). For the DNA purification step, an aliquot of isolated exosomes was lysed in 300pl lysis buffer that was part of the MirVana RNA isolation kit (Ambion) and the DNAs were purified from the lysed mixture using a DNA purification kit (Qiagen) according to the manufacturer’s recommendation.

[0090] To examine whether the extracted DNA contains common genes, PCRs were performed using primer pairs specific to GAPDH, Human endogenous retrovirus K, Tenascin-c and Line-1. For the GAPDH gene, the following primers were used: Forw3GAPDHnew (SEQ ID NO: 1) and Rev3GAPDHnew (SEQ ID NO: 2). The primer pair amplifies a 112bp amplicon if the template is a spliced GAPDH cDNA and a 216bp amplicon if the template is an un-spliced genomic GAPDH DNA. In one experiment, isolated exosomes were treated with DNase before being lysed for DNA extraction (FIG. 3a). The 112bp fragments were amplified as expected from the exosomes from the tumor serum (See Lane 4 in FIG. 3a) and the primary tumor cells (See Lane 6 in FIG. 3a) but not from the exosomes from normal human fibroblasts (See Lane 5 in FIG. 3a). The 216bp fragment could not be amplified from exosomes of all three origins. However, fragments of both 112bp and 216bp were amplified when the genomic DNA isolated from the glioblastoma cell was used as templates (See Lane 3 in FIG. 3a). Thus, spliced GAPDH DNA exists within exosomes isolated from tumor cells but not within exosomes isolated from normal fibroblast cells.

[0091] In contrast, in another experiment, isolated exosomes were not treated with DNase before being lysed for DNA extraction (FIG. 3b). Not only the 112bp fragments but also the 216bp fragments were amplified from exosomes isolated from primary melanoma cells (See Lane 3 in FIG. 3b), suggesting that non-spliced GAPDH DNA or partially spliced cDNA that has been reverse transcribed exists outside of the exosomes.

[0092] For the Human Endogenous Retrovirus K (HERV-K) gene, the following primers were used: HERVK_6Forw (SEQ ID NO: 3) and HERVK_6Rev (SEQ ID NO: 4). The primer pair amplifies a 172bp amplicon. DNA was extracted from exosomes that were isolated and treated with DNase, and used as the template for PCR amplification. As shown

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2017272272 07 Dec 2017 in FIG. 3c, 172bp fragments were amplified in all tumor and normal human serum exosomes but not in exosomes from normal human fibroblasts. These data suggest that unlike exosomes from normal human fibroblasts, tumor and normal human serum exosomes contain endogenous retrovirus DNA sequences. To examine if tumor exosomes also contain transposable elements, the following LINE-1 specific primers were used for PCR amplifications: Linel_Forw (SEQ ID NO: 5) and Linel_Rev (SEQ ID NO: 6). These two primers are designed to detect LINE-1 in all species since each primer contains equal amounts of two different oligos. For the Linel_Forw primer, one oligo contains a C and the other oligo contains a G at the position designated with “s”. For the Linel_Rev primer, one oligo contains an A and the other oligo contains a G at the position designated with “r”. The primer pair amplifies a 290bp amplicon. The template was the DNA extracted from exosomes that were treated with DNase (as described above). As shown in FIG. 3e, 290bp LINE-1 fragments could be amplified from the exosomes from tumor cells and normal human serum but not from exosomes from the normal human fibroblasts.

[0093] To test if exosomes also contain Tenascin-C DNA, the following primer pair was used to perform PCR: Tenascin C Forw (SEQ ID NO: 7) and Tenascin C Rev (SEQ ID NO: 8). The primer pair amplifies a 197bp amplicon. The template was the DNA extracted from exosomes that were isolated and then treated with DNase before lysis. As shown in FIG. 3d, 197bp Tenascin C fragments were amplified in exosomes from tumor cells or normal human serum but not in exosomes from normal human fibroblasts. Thus, Tenascin-C DNA exists in tumor and normal human serum exosomes but not in exosomes from normal human fibroblasts.

[0094] To further confirm the presence of DNA in exosomes, exosomal DNA was extracted from D425 medulloblastoma cells using the method described above. Specifically, the exosomes were isolated and treated with DNase before lysis. Equal volumes of the final DNA extract were either treated with DNase or not treated with DNase before being visualized by Ethidium Bromide staining in 1% agarose gel. Ethidium Bromide is a dye that specifically stains nucleic acids and can be visualized under ultraviolet light. As shown in FIG. 3f, Ethidium Bromide staining disappeared after DNase treatment (See Lane 3 in FIG. 3f) while strong staining could be visualized in the un-treated aliquot (See Lane 2 in FIG. 3f). The DNase treated and non-treated extracts were also analyzed on a RNA pico chip (Agilent Technologies). As shown in FIG. 3g, single stranded DNA could be readily detected in the

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DNase-non-treated extract (See upper panel in FIG. 3g) but could barely be detected in the DNase-treated extract (See lower panel in FIG. 3g).

[0095] To test whether the extracted DNA was single-stranded, nucleic acids were extracted from the treated exosomes as described in the previous paragraph and further treated with RNAse to eliminate any RNA contamination. The treated nucleic acids were then analyzed on a RNA pico Bioanalyzer chip and in a DNA 1000 chip. The RNA pico chip only detects single stranded nucleic acids. The DNA 1000 chip detected double stranded nucleic acids. As shown in FIG. 3h, single stranded nucleic acids were detected (See upper panel) but double stranded nucleic acids were not detected (See lower panel). Thus, the DNA contained within tumor exosomes are mostly single stranded.

[0096] To demonstrate that single stranded DNA exists in tumor cells but not in normal human fibroblasts, nucleic acids were extracted from exosomes from either glioblastoma patient serum or normal human fibroblasts. The exosomes were treated with DNase before lysis and the purified nucleic acids were treated with RNase before analysis. As shown in FIG. 3i, exosomal nucleic acids extracted from glioblastoma patient serum could be detected by a RNA pico chip. In contrast, only a very small amount of single stranded DNA was extracted from normal human fibroblasts.

[0097] Accordingly, exosomes from tumor cells and normal human serum were found to contain contain single-stranded DNA. The single-stranded DNA is a reverse transcription product since the amplification products do not contain introns (FIG. 3a and FIG. 3b). It is known that tumor cells as well as normal progenitor cells/stem cells have active reverse transcriptase (RT) activity although the activity in normal progenitor cells/stem cells is relatively much lower. This RT activity makes it plausible that RNA transcripts in the cell can be reverse transcribed and packaged into exosomes as cDNA. Interestingly, exosomes from tumor cells contain more cDNAs corresponding to tumor-specific gene transcripts since tumor cells usually have up-regulated reverse transcriptase activity. Therefore, tumor specific cDNA in exosomes may be used as biomarkers for the diagnosis or prognosis of different tumor types. The use of cDNAs as biomarkers would skip the step of reverse transcription compared to the used of mRNA as biomarkers for tumors. In addition, the use of exosomal cDNA is advantageous over the use of whole serum/plasma DNA because serum/plasma contains genomic DNA released from dying cells. When testing amplified whole serum/plasma DNA, there will be more background.

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Example 4: Most extracellular RNA in human serum is contained within exosomes.

[0098] To determine the amount of RNA circulating in serum as “free RNA”/RNAprotein complex versus the amount of RNA contained within the exosomes, we isolated serum from a healthy human subject, and evenly split the serum into two samples with equal volume. For sample 1, the serum was ultracentrifuged to remove most micro vesicles. Then the serum supernatant was collected and RNA left in the supernatant was extracted using Trizol LS. For sample 2, the serum was not ultracentrifuged and total RNA was extracted from the serum using Trizol LS. The amount of RNA in the sample 1 supernatant and sample 2 serum was measured. As a result, it was found that the amount of free RNA in sample 1 supernatant was less than 10% of the amount of total RNA isolated from the serum sample 2. Therefore, a majority of the RNA in serum is associated with the exosomes.

Example 5: High efficiency of serum extracellular nucleic acid extraction is achieved by incorporating a serum exosome isolation step.

[0099] Whole serum and plasma contain large amounts of circulating DNA and possibly also RNA protected in protein complexes, while free RNA have a half-life of a few minutes in serum. Extracellular nucleic acid profiles in serum vary between normal and diseased mammals and thus may be biomarkers for certain diseases. To examine the profiles, nucleic acids need to be extracted. However, direct extraction of nucleic acids from serum and plasma is not practical, especially from large serum/plasma volumes. In this case, large volumes of Trizol LS (a RNA extraction reagent) are used to instantly inactivate all serum nucleases before extracting the exosomal nucleic acids. Subsequently, contaminants precipitate into the sample and affect subsequent analyses. As shown in Example 4, most extracellular RNAs in serum are contained in serum exosomes. Therefore, we tested whether it is more efficient to isolate extracellular nucleic acids by isolating the serum exosomes before nucleic acid extraction.

[00100] Four milliliter (ml) blood serum from a patient was split into 2 aliquots of 2 ml each. Serum exosomes from one aliquot were isolated prior to RNA extraction. The methods of exosome isolation and RNA extraction are the same as mentioned in Example 2. For the other aliquot, RNA was extracted directly using Trizol LS according to manufacturer’s recommendation. The nucleic acids from these two extractions were analyzed on a Bioanalyzer RNA chip (Agilent Technologies). As shown in Figure 4, the amount of RNA extracted with the former method is significantly more than that obtained from the latter

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2017272272 07 Dec 2017 method. Further, the quality of RNA extracted with the latter method is relatively poor compared to that with the former method. Thus, the step of exosome isolation contributes to the efficiency of extracellular RNA extraction from serum.

Example 6: Microarray analysis of mRNA.

[00101] Microarray analysis of the mRNA population in glioblastoma cells and microvesicles derived from them was performed by Miltenyi Biotech (Auburn, CA, USA) using the Agilent Whole Human Genome Microarray, 4x44K, two color array. The microarray analysis was performed on two different RNA preparations from primary glioblastoma cells and their corresponding microvesicles RNA preparations prepared as described in Examples 1 and 2. The data was analyzed using the GeneSifter software (Vizxlabs, Seattle, WA, USA). The Intersector software (Vizxlabs) was used to extract the genes readily detected on both arrays. The microarray data have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO series accession number GSE13470.

[00102] We found approximately 22,000 gene transcripts in the cells and 27,000 gene transcripts in the microvesicles that were detected well above background levels (99% confidence interval) on both arrays. Approximately 4,700 different mRNAs were detected exclusively in microvesicles on both arrays, indicating a selective enrichment process within the micro vesicles. Consistent with this, there was a poor overall correlation in levels of mRNAs in the microvesicles as compared to their cells of origin from two tumor cell preparations (FIGS. 2a and 2b). In contrast, there was a good correlation in levels of mRNA from one cell culture (A) versus the second cell culture (B) (FIG. 2c) and a similar correlation in levels of mRNA from the corresponding microvesicles (A) and (B) (FIG. 2d).

Accordingly, there is a consistency of mRNA distribution within the tumor cells and micro vesicles. In comparing the ratio of transcripts in the micro vesicles versus their cells of origin, we found 3,426 transcripts differentially distributed more than 5-fold (p-value <0.01). Of these, 2,238 transcripts were enriched (up to 380 fold) and 1,188 transcripts were less abundant (up to 90 fold) than in the cells (FIG. 5). The intensities and ratios of all gene transcripts were documented. The ontologies of mRNA transcripts enriched or reduced more than 10-fold were recorded and reviewed.

[00103] The mRNA transcripts that were highly enriched in the microvesicles were not always the ones that were most abundant in the micro vesicles. The most abundant transcripts

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2017272272 07 Dec 2017 would be more likely to generate an effect in the recipient cell upon delivery, and therefore the 500 most abundant mRNA transcripts present in microvesicles were divided into different biological processes based on their ontology descriptions (FIG. 6a). Of the various ontologies, angiogenesis, cell proliferation, immune response, cell migration and histone modification were selected for further study as they represent specific functions that could be involved in remodeling the tumor stroma and enhancing tumor growth. Glioblastoma microvesicle mRNAs belonging to these five ontologies were plotted to compare their levels and contribution to the mRNA spectrum (FIG. 6b). All five ontologies contained mRNAs with very high expression levels compared to the median signal intensity level of the array.

[00104] A thorough analysis of mRNAs that are enriched in the microvesicles versus donor cells, suggests that there may be a cellular mechanism for localizing these messages into micro vesicles, possibly via a “zip code” in the 3’UTR as described for mRNAs translated in specific cellular locations, such as that for beta actin (Kislauskis et al., 1994). The conformation of the mRNAs in the microvesicles is not known, but they may be present as ribonuclear particles (RNPs) (Mallardo et al., 2003) which would then prevent degradation and premature translation in the donor cell.

[00105] Microarray analysis of the mRNA populations in glioblastoma cells and microvesicles derived from glioblastoma cells, melanoma cells, and microvesicles derived from melanoma cells was performed by Illumina Inc. (San Diego, CA, USA) using the Whole-Genome cDNA-mediated Annealing, Selection, Extension, and Ligation (DASL) Assay. The Whole-Genome DASL Assay combines the PCR and labeling steps of Illumina’s DASL Assay with the gene-based hybridization and whole-genome probe set of Illumina’s HumanRef-8 BeadChip. This BeadChip covers more than 24,000 annotated genes derived from RefSeq (Build 36.2, Release 22). The microarray analysis was performed on two different RNA preparations from primary glioblastoma cells, micro vesicles from glioblastomas cells (derived with the method as described in Examples 1 and 2), melanoma cells, and microvesicles from melanoma cells (derived with the method as described in Examples 1 and 2).

[00106] The expression data for each RNA preparation were pooled together and used to generate a cluster diagram. As shown in FIG. 7, mRNA expression profiles for glioblastoma cells, microvesicles from glioblastomas cells, melanoma cells, and microvesicles from melanoma cells are clustered together, respectively. Expression profiles of the two primary glioblastoma cell lines 20/3C and ll/5c are clustered with a distance of about 0.06.

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Expression profiles of the two primary melanoma cell lines 0105C and 0664C are clustered with a distance of about 0.09. Expression profiles of exosomes from the two primary melanoma cell lines 0105C and 0664C are clustered together with a distance of around 0.15. Expression profiles of exosomes from the two primary glioblastomas cell lines 20/3C and ll/5c are clustered together with a distance of around 0.098. Thus, exosomes from glioblastoma and melanoma have distinctive mRNA expression signatures and the gene expression signature of exosomes differs from that of their original cells. These data demonstrate that mRNA expression profiles from micro vesicles may be used in the methods described herein for the diagnosis and prognosis of cancers.

Example 7: Glioblastoma microvesicles contain miRNA [00107] Mature miRNA from microvesicles and from donor cells was detected using a quantitative miRNA reverse transcription PCR. Specifically, total RNA was isolated from microvesicles and from donor cells using the mirVana RNA isolation kit (Applied Biosystems, Foster City, CA, USA). Using the TaqMan® MicroRNA Assay kits (Applied Biosystems, Foster City, CA, USA), 30 ng total RNA was converted into cDNA using specific miR-primers and further amplified according to the manufacturer’s protocol.

[00108] A subset of 11 miRNAs among those known to be up-regulated and abundant in gliomas was analyzed in microvesicles purified from two different primary glioblastomas (GBM 1 and GBM 2). These subset contained let-7a, miR-15b, miR-16, miR-19b, miR-21, miR-26a, miR-27a, miR-92, miR-93, miR-320 and miR-20. All of these miRNA were readily detected in donor cells and in microvesicles (FIG. 8). The levels were generally lower in microvesicles per pg total RNA than in parental cells (10%, corresponding to approximately 3 Ct-values), but the levels were well correlated, indicating that these 11 miRNA species are not enriched in micro vesicles.

[00109] Microarray analysis of the microRNA populations in glioblastoma cells and microvesicles derived from glioblastoma cells, melanoma cells, and microvesicles derived from melanoma cells was performed by Illumina Inc. (San Diego, CA, USA) using the MicroRNA Expression Profiling Panel, powered by the DASL Assay. The human MicroRNA Panels include 1146 microRNA species. The microarray analysis was performed on two different RNA preparations from primary glioblastoma cells, micro vesicles from glioblastomas cells (derived using the method described in Examples 1 and 2), melanoma

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2017272272 07 Dec 2017 cells, and microvesicles from melanoma cells (derived using the method described in Examples 1 and 2).

[00110] The expression data for each RNA preparation were pooled together and used to generate a cluster diagram. As shown in FIG. 9, microRNA expression profiles for glioblastoma cells, microvesicles from glioblastomas cells, melanoma cells, and microvesicles from melanoma cells are clustered together, respectively. Expression profiles of the two primary melanoma cell lines 0105C and 0664C are clustered with a distance of about 0.13. Expression profiles of the two primary glioblastomas cell lines 20/3C and ll/5c are clustered with a distance of about 0.12. Expression profiles of exosomes from the two primary glioblastomas cell lines 20/3C and 1 l/5c are clustered together with a distance of around 0.12. Expression profiles of exosomes from the two primary melanoma cell lines 0105C and 0664C are clustered together with a distance of around 0.17. Thus, exosomes from glioblastoma and melanoma have distinctive microRNA expression signatures and that the gene expression signature of exosomes differs from that of their original cells. Furthermore, as demonstrated herein, microRNA expression profiles from microvesicles may be used in the methods described herein for the diagnosis and prognosis of cancers.

[00111] The finding of miRNAs in microvesicles suggests that tumor-derived microvesicles can modify the surrounding normal cells by changing their transcriptional/translational profiles. Furthermore, as demonstrated herein, miRNA expression profile from microvesicles may be used in the methods described herein for the diagnosis and prognosis of cancers, including but not limited to glioblastoma.

Examples 8-15. These examples show that nucleic acids within exosomes from bodily fluids can be used as biomarkers for diseases or other medical conditions.

Example 8: Expression profiles of miRNAs in microvesicles can be used as sensitive biomarkers for glioblastoma.

[00112] To determine if microRNAs within exosomes may be used as biomarkers for a disease and/or medical condition, we examined the existence of a correlation between the expression level of microRNA and disease status. Since microRNA-21 is expressed at high levels in glioblastoma cells and is readily detectable in exosomes isolated from serum of glioblastoma patients, we measured quantitatively microRNA-21 copy numbers within exosomes from the sera of glioblastoma patients by quantitative RT-PCR. Specifically, exosomes were isolated from 4 ml serum samples from 9 normal human subjects and 9

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2017272272 07 Dec 2017 glioblastoma patients. The RNA extraction procedure was similar to the RNA extraction procedure as described in Example 2. The level of miR-21 was analyzed using singleplex qPCR (Applied Biosystems) and normalized to GAPDH expression level.

[00113] As shown in FIG. 10, the average Ct-value was 5.98 lower in the glioblastoma serum sample, suggesting that the exosomal miRNA-21 expression level in glioblastoma patients is approximately 63 fold higher than that in a normal human subject. The difference is statistically significant with a p value of 0.01. Therefore, there is a correlation between microRNA-21 expression level and glioblastoma disease status, which demonstrates that validity and applicability of the non-invasive diagnostic methods disclosed herein. For example, in one aspect, the method comprised the steps of isolating exosomes from the bodily fluid of a subject and analyzing microRNA-21 expression levels within the exosomes by measuring the copy number of microRNA-21 and comparing the number to that within exosomes from a normal subject or to a standard number generated by analyzing microRNA-21 contents within exosomes from a group of normal subjects. An increased copy number indicates the existence of glioblastoma in the subject; while the absence of an increased copy number indicates the absence of glioblastoma in the subject. This basic method may be extrapolated to diagnose/monitor other diseases and/or medical conditions associated with other species of microRNAs.

Example 9: mRNAs in microvesicles can be used as sensitive biomarkers for diagnosis [00114] Nucleic acids are of high value as biomarkers because of their ability to be detected with high sensitivity by PCR methods. Accordingly, the following tests were designed and carried out to determine whether the mRNA in microvesicles could be used as biomarkers for a medical disease or condition, in this case glioblastoma tumors. The epidermal growth factor receptor (EGFR) mRNA was selected because the expression of the EGFRvIII mutation is specific to some tumors and defines a clinically distinct subtype of glioma (Pelloski et al., 2007). In addition, EGFRvIII mutations traditionally cannot be detected using tissues other than the lesion tissues since these mutations are somatic mutations but not germ line mutations. Therefore, a biopsy from lesion tissues such as glioma tumor is conventionally required for detecting EGFRvIII mutations. As detailed below, nested RT-PCR was used to identify EGFRvIII mRNA in glioma tumor biopsy samples and the results compared with the mRNA species found in microvesicles purified from a serum sample from the same patient.

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2017272272 07 Dec 2017 [00115] Microvesicles were purified from primary human glioblastoma cells followed by RNA extraction from both the microvesicles and donor cells (biopsy). The samples were coded and the PCRs were performed in a blind fashion. Gli-36EGFRvIII (human glioma cell stably expressing EGFRvIII) was included as a positive control. The microvesicles from 0.52 ml of frozen serum samples were pelleted as described in Example 2 and the RNA was extracted using the MirVana Micro vesicles RNA isolation kit. Nested RT-PCR was then used to amplify both the wild type EGFR (1153 bp) and EGFRvIII (352 bp) transcripts from both the microvesicles and donor cells using the same set of primers. Specifically, the RNA was converted to cDNA using the Omniscript RT kit (Qiagen Inc, Valencia, CA, USA) according to the manufacturer’s recommended protocol. GAPDH primers were GAPDH Forward (SEQ ID NO: 9) and GAPDH Reverse (SEQ ID NO: 10). The EGFR/EGFRvIII PCR1 primers were SEQ ID NO: 11 and SEQ ID NO: 12. The EGFR/EGFRvIII PCR2 primers were SEQ ID NO: 13 and SEQ ID NO: 14. The PCR cycling protocol was 94 °C for 3 minutes; 94 °C for 45 seconds, 60 °C for 45 seconds, 72 °C for 2 minutes for 35 cycles; and a final step 72 °C for 7 minutes.

[00116] We analyzed the biopsy sample to determine whether the EGFRvIII mRNA was present and compared the result with RNA extracted from exosomes purified from a frozen serum sample from the same patient. Fourteen of the 30 tumor samples (47%) contained the EGFRvIII transcript, which is consistent with the percentage of glioblastomas found to contain this mutation in other studies (Nishikawa et al., 2004). EGFRvIII could be amplified from exosomes in seven of the 25 patients (28%) from whom serum was drawn around the time of surgery (FIG. 11 and Table 1). When a new pair of primers EGFR/EGFRvIII PCR3: SEQ ID NO: 15 and SEQ ID NO: 16, were used as the second primer pair for the above nested PCR amplification, more individuals were found to harbor EGFRvIII mutations (Table 1). EGFRvIII could be amplified from exosomes in the six patients who was identified as negatives with the old pair of primers EGFRvIII PCR2: SEQ ID NO: 13 AND SEQ ID NO: 14. Notably, exosomes from individual 13, whose biopsy did not show EGFRvIII mutation, was shown to contain EGFRvIII mutation, suggesting an increased sensivity of EGFRvIII mutation detection using exosomes technology. From the exosomes isolated from 52 normal control serum samples, EGFRvIII could not be amplified (FIG. 12). Interestingly, two patients with an EGFRvIII negative tumor sample turned out to be EGFRvIII positive in the serum exosomes, supporting heterogeneous foci of EGFRvIII expression in the glioma tumor. Furthermore, our data also showed that intact RNAs in microvesicles were, unexpectedly,

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2017272272 07 Dec 2017 able to be isolated from frozen bodily serum of glioblastoma patients. These blind serum samples from confirmed glioblastoma patients were obtained from the Cancer Research Center (VU medical center, Amsterdam, the Netherlands) and were kept at -80°C until use. The identification of tumor specific RNAs in serum microvesicles allows the detection of somatic mutations which are present in the tumor cells. Such technology should result in improved diagnosis and therapeutic decisions.

[00117] The RNA found in the microvesicles contains a “snapshot” of a substantial array of the cellular gene expression profile at a given time. Among the mRNA found in glioblastoma-derived microvesicles, the EGFR mRNA is of special interest since the EGFRvIII splice variant is specifically associated with glioblastomas (Nishikawa et al.,

2004) . Here it is demonstrated that brain tumors release micro vesicles into the bloodstream across the blood-brain-barrier (BBB), which has not been shown before. It is further demonstrated that mRNA variants, such as EGFRvIII in brain tumors, are able to be detected by a method comprising the steps of isolating exosomes from a small amount of patient serum and analyzing the RNA in said micro vesicles.

[00118] Knowledge of the EGFRvIII mutation in tumors is important in choosing an optimal treatment regimen. EGFRvIII-positive gliomas are over 50 times more likely to respond to treatment with EGFR-inhibitors like erlotinib or gefitinib (Mellinghoff et al.,

2005) .

Example 10: Diagnosis of iron metabolism disorders [00119] The exosome diagnostics method can be adapted for other purposes as shown by the following example.

[00120] Hepcidin, an antimicrobial peptide, is the master hormonal regulator of iron metabolism. This peptide is produced mainly in mammalian liver and is controlled by the erythropoietic activity of the bone-marrow, the amount of circulating and stored body iron, and inflammation. Upon stimulation, hepcidin is secreted into the circulation or urine where it may act on target ferroportin-expressing cells. Ferroportin is the sole iron exporter identified to date and when bound to hepcidin, it is internalized and degraded. The resulting destruction of ferroportin leads to iron retention in ferroportin expressing cells such as macrophages and enterocytes. This pathophysiological mechanism underlies anemia of chronic diseases. More specifically, inappropriately high levels of hepcidin and elevated iron content within the reticuloendothelial system characterize anemia. Indeed, anemia may be

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2017272272 07 Dec 2017 associated with many diseases and/or medical conditions such as infections (acute and chronic), cancer, autoimmune, chronic rejection after solid-organ transplantation, and chronic kidney disease and inflammation (Weiss and Goodnough, 2005). On the other hand, in a genetic iron overload disease such as hereditary hemochromatosis, inappropriately low expression levels of hepcidin encourage a potentially fatal excessive efflux of iron from within the reticuloendothelial system. So, hepcidin is up-regulated in anemia associated with chronic disease, but down-regulated in hemochromatosis.

[00121] Currently, there is no suitable assay to quantitatively measure hepcidin levels in circulation or urine (Kemna et al., 2008) except time-of-flight mass spectrometry (TOF MS), which needs highly specialized equipment, and therefore is not readily accessible. Recently, the method of Enzyme Linked ImmunoSorbent Assay (ELISA) has been proposed to quantitatively measure hepcidin hormone levels but this method is not consistent because of the lack of clear correlations with hepcidin (Kemna et al., 2005; Kemna et al., 2007) and other iron related parameters (Brookes et al., 2005; Roe et al., 2007).

[00122] Hepcidin mRNA was detected in exosomes from human serum, as follows. Exosomes were first isolated from human serum and their mRNA contents extracted before conversion to cDNA and PCR amplification. PCR primers were designed to amplify a 129 nucleotide fragment of human Hepcidin. The sequences of the primers are SEQ ID NO: 57 and SEQ ID NO: 58. A hepcidin transcript of 129 nucleotides (the middle peak in FIG. 13D) was readily detected by Bioanalyzer. As a positive control (FIG. 13B), RNA from a human hepatoma cell line Huh-7 was extracted and converted to cDNA. The negative control (FIG. 13C) is without mRNA. These Bioanalyzer data are also shown in the pseudogel in FIG. 13A.

[00123] Hepcidin mRNA in microvesicles in circulation correlates with hepcidin mRNA in liver cells. Hence, measuring hepcidin mRNA within micro vesicles in a bodily fluid sample would allow one to diagnose or monitor anemia or hemochromatosis in the subject.

[00124] Thus, it is possible to diagnose and/or monitor anemia and hemochromatosis in a subject by isolating microvesicles from a bodily fluid and comparing the hepcidin mRNA in said microvesicles with the mRNA from from a normal subject. With an anemic subject, the copy number of mRNA is increased over the normal, non-anemic level. In a subject suffering from hemochromatosis, the copy number is decreased relative to the mRNA in a normal subject.

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Example 11: Non-invasive transcriptional profiling of exosomes for diabetic nephropathy diagnosis [00125] Diabetic nephropathy (DN) is a life threatening complication that currently lacks specific treatments. Thus, there is a need to develop sensitive diagnostics to identify patients developing or at risk of developing DN, enabling early intervention and monitoring.

[00126] Urine analysis provides a way to examine kidney function without having to take a biopsy. To date, this analysis has been limited to the study of protein in the urine.

This Example sets forth a method to obtain from urine transcriptional profiles derived from cells that normally could only be obtained by kidney biopsy. Specifically, the method comprises the steps of isolating urine exosomes and analyzing the RNAs within said exosomes to obtain transcriptional profiles, which can be used to examine molecular changes being made by kidney cells in diabetic individuals and provide a 'snap shot' of any new proteins being made by the kidney. State-of-the-art technologies to obtain exosomal transcription profiles include, but are not limited to, contemporary hybridization arrays, PCR based technologies, and next generation sequencing methods. Since direct sequencing does not require pre-designed primers or spotted DNA oligos, it will provide a non-biased description of exosomal RNA profiles. An example of next generation sequencing technology is provided by the Illumina Genome Analyzer, which utilizes massively parallel sequencing technology which allows it to sequence the equivalent of 1/3 a human genome per run. The data obtainable from this analysis would enable one to rapidly and comprehensively examine the urinary exosomal transcriptional profile and allow comparison to the whole kidney. Using such a method, one could obtain much needed information regarding the transcription profile of urinary exosomes. A comparison of transcripts in control versus diabetes-derived urinary exosomes could further provide one with a comprehensive list of both predicted and new biomarkers for diabetic nephropathy.

[00127] In order to prove the feasibility of the diagnostic method described above, an experiment was designed and carried out to isolate urinary exosomes and to confirm the presence of renal specific biomarkers within these exosomes. In this experiment, a fresh morning urine sample of 220 ml was collected from a 28-year old healthy male subject and processed via differential centrifugation to isolate urinary exosomes. Specifically, urine was first spun at 300 x g spin for 10 minutes to remove any cells from the sample. The supernatant was collected and then underwent a 20-minute 16,500 x g spin to bring down any cell debris or protein aggregates. The supernatant was then passed through a 0.22 uM

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2017272272 07 Dec 2017 membrane filter to remove debris with diameters larger than 0.22uM. Finally, the sample underwent ultra-centrifugation at 100,000 x g for 1 hour to pellet the exosomes (Thery et al.,

2006). The pellet was gently washed in phosphate buffered saline (PBS) and RNA was extracted using a Qiagen RNeasy kit pursuant to the manufacturer’s instructions. The isolated RNA was converted to cDNA using the Omniscript RT kit (Qiagen) followed by PCR amplification of renal specific genes.

[00128] The renal specific genes examined and their corresponding renal area where the gene is expressed are as follows: AQP1 - proximal tubules; AQP2 - distal tubule (principal cells); CUBN - proximal tubules; LRP2 - proximal tubules; AVPR2 - proximal and distal tubules; SLC9A3 (NHE-3) - Proximal tubule; ATP6V1B1 - distal tubule (intercalated cells); NPHS1 - glomerulus (podocyte cells); NPHS2 - glomerulus (podocyte cells); and CLCN3 Type B intercalated cells of collecting ducts. The sequences of the primers designed to amplify each gene are AQP1-F (SEQ ID NO: 17) and AQP1-R (SEQ ID NO: 18); AQP2-F (SEQ ID NO: 19) and AQP2-R (SEQ ID NO: 20); CUBN-F (SEQ ID NO: 21) and CUBN-R (SEQ ID NO: 22); LRP2-F (SEQ ID NO: 23) and LRP2-R (SEQ ID NO: 24); AVPR2-F (SEQ ID NO: 25) and AVPR2-R (SEQ ID NO: 26); SLC9A3-F (SEQ ID NO: 27) and SLC9A3-R (SEQ ID NO: 28); ATP6V1B1-F (SEQ ID NO: 29) and ATP6V1B1-R (SEQ ID NO: 30); NPHS1-F (SEQ ID NO: 31) and NPHS1-R (SEQ ID NO: 32); NPHS2-F (SEQ ID NO: 33) and NPHS2-R (SEQ ID NO: 34); CLCN5-F (SEQ ID NO: 35) and CLCN5-R (SEQ ID NO: 36).

[00129] The expected sizes of the PCR products for each gene are AQPl-226bp, AQP2208bp, CUBN-285bp, LRP2-220bp, AVPR2-290bp, SLC9A3-200bp, ATP6VlBl-226bp, NPHSl-201bp, NPHS2-266bp and CLCN5-204bp. The PCR cycling protocol was 95 °C for 8 minutes; 95 °C for 30 seconds, 60 °C for 30 seconds, 72 °C for 45 seconds for 30 cycles; and a final step 72 °C for 10 minutes.

[00130] As shown in FIG. 14a, kidney tubule cells contain multivesicular bodies, which is an intermediate step during exosome generation. Exosomes isolated from these cells can be identified by electron microscopy (FIG. 14b). Analysis of total RNA extracted from urinary exosomes indicates the presence of RNA species with a broad range of sizes (FIG. 14c). 18S and 28S ribosomal RNAs were not found. PCR analysis confirmed the presence of renal specific transcripts within urinary exosomes (FIG. 14d). These data show that kidney cells shed exosomes into urine and these urinary exosomes contain transcripts of renal

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2017272272 07 Dec 2017 origin, and that the exosome method can detect renal biomarkers associated with certain renal diseases and/or other medical conditions.

[00131] To further confirm the presence of renal specific mRNA transcripts in urinary exosomes, an independent set of experiments were performed using urine samples from six individuals. Exosomal nucleic acids were extracted from 200ml morning urine samples from each indivisual following a procedure as mentioned above. Specifically, urine samples underwent differential centrifugation starting with a 1000 xg centrifugation to spin down whole cells and cell debris. The supernatant was carefully removed and centrifuged at 16,500 xg for 20 minutes. The follow-on supernatant was then removed and filtered through a 0.8pm filter to remove residual debris from the exosome containing supernatant. The final supernatant then underwent ultracentrifugation at 100,000 xg for lhr lOmin. The pellet was washed in nuclease free PBS and re-centrifuged at 100,000 xg for lhr lOmin to obtain the exosomes pellet which is ready for nucleic acid extraction. Nucleic acids were extracted from the pelleted exosomes using the Arcturus PicoPure RNA Isolation kit and the nucleic acid concentration and integrity was analyzed using a Bioanalyzer (Agilent) Pico chip. As shown in FIG. 14e, nucleic acids isolated from urinary exosomes vary from individual to individual. To test whether the presence of renal biomarkers also varies from individual to individual, PCR amplifications were carried out for Aquaporinl, Aquaporin2 and Cubilin gene using a new set of primer pairs: AQP1 new primer pair: SEQ ID NO: 37 and SEQ ID NO: 38; AQP2 new primer pair: SEQ ID NO: 39 and SEQ ID NO: 40; CUBN new primer pair: SEQ ID NO: 41 and SEQ ID NO: 42. These primer pairs were designed specifically to amplify the spliced and reverse transcribed cDNA fragments. Reverse transcription was performed using the Qiagen Sensiscript kit. As shown in FIG. 14f, no amplification was seen in individual 1, probably due to failed nucleic acid extraction. AQP1 was amplified only in individual 2. CUBN was amplified in indivisual 2 and 3. And AQP2 was amplified in individual 2, 3, 4 and 5. In comparison actin gene (indicated by “House” in FIG. 14f) was amplified in individual 2, 3, 4, 5 and 6. These data provide more evidence that urinary exosomes contain renal specific mRNA transcripts although the expression levels are different between different individuals.

[00132] To test the presence of cDNAs in urinary exosomes, a 200ml human urine sample was split into two 100ml urine samples. Urinary exosomes were isolated from each sample. Exosomes from one sample were treated with DNase and those from the other sample were mock treated. Exosomes from each sample were then lysed for nucleic acid

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2017272272 07 Dec 2017 extraction using PicoPure RNA isolation kit (Acturus). The nucleic acids were used as templates for nested-PCR amplification (PCR protocols described in Example 9) without prior reverse transcription. The primer pairs to amplify the actin gene were Actin-FOR (SEQ ID NO: 43) and Actin-REV (SEQ ID NO: 44); Actin-nest-FOR (SEQ ID NO: 45) and Actinnest-REV (SEQ ID NO: 46) with an expected final amplicon of lOObp based on the actin gene cDNA sequence. As shown in FIG. 14g, the lOObp fragments were present in the positive control (human kidney cDNA as templates), DNase treated and non-treated exosomes, but absent in the negative control lane (without templates). Accordingly, actin cDNA is present in both the DNase treated and non-treated urinary exosomes.

[00133] To test whether most nucleic acids extracted using the method were present within exosomes, the nucleic acids extracted from the DNase treated and non-treated exosomes were dissolved in equal volumes and analyzed using a RNA Pico chip (Agilent Technologies). As shown in FIG. 14h, the concentration of the isolated nucleic acids from the DNase treated sample was 1,131 pg/ul and that from the non-treated sample was 1,378 pg/ul. Thus, more than 80% nucleic acids extracted from urinary exosomes using the above method were from inside exosomes.

[00134] To identify the content of urinary exosomes systematically, nucleic acids were extracted from urinary exosomes and submitted to the Broad Institute for sequencing. Approximately 14 million sequence reads were generated, each 76 nucleotides in length. These sequence reads correspond to fragments of DNA/RNA transcripts present within urinary exosomes. Using an extremely strict alignment parameter (100% identity over full length sequence), approximately 15% of the reads were aligned to the human genome. This percentage would likely increase if less stringent alignment criteria was used. A majority of these 15% reads did not align with protein coding genes but rather with non-coding genomic elements such are transposons and various LINE & SINE repeat elements. Notably, for those reads that are not aligned to the human genome, many are aligned to viral sequences. To the extent that the compositions and levels of nucleic acids contained in urinary exosomes change with respect to a disease status, profiles of the nucleic acids could be used according to the present methods as biomarkers for disease diagnosis.

[00135] This example demonstrates that the exosome method of analyzing urine exosomes can be used to determine cellular changes in the kidney in diabetes-related kidney disease without having to take a high-risk, invasive renal biopsy. The method provides a new and sensitive diagnostic tool using exosomes for early detection of kidney diseases such as

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2017272272 07 Dec 2017 diabetic nephropathy. This will allow immediate intervention and treatment. In sum, the exosome diagnostic method and technology described herein provides a means of muchneeded diagnostics for diabetic nephropathy and other diseases which are associated with certain profiles of nucleic acids contained in urinary exosomes.

Example 12: Prostate cancer diagnosis and urinary exosomes [00136] Prostate cancer is the most common cancer in men today. The risk of prostate cancer is approximately 16%. More than 218,000 men in the United States were diagnosed in 2008. The earlier prostate cancer is detected, the greater are the chances of successful treatment. According to the American Cancer Society, if prostate cancers are found while they are still in the prostate itself or nearby areas, the five-year relative survival rate is over 98%.

[00137] One established diagnostic method is carried out by measuring the level of prostate specific antigen (PSA) in the blood, combined with a digital rectal examination. However, both the sensitivity and specificity of the PSA test requires significant improvement. This low specificity results in a high number of false positives, which generate numerous unnecessary and expensive biopsies. Other diagnostic methods are carried out by detecting the genetic profiles of newly identified biomarkers including, but not limited to, prostate cancer gene 3 (PCA3) (Groskopf et al., 2006; Nakanishi et al., 2008), a fusion gene between transmembrane protease serine 2 and ETS-related gene (TMPRSS2-ERG) (Tomlins et al., 2005), glutathione S-transferase pi (Goessl et al., 2000; Gonzalgo et al., 2004), and alpha-methylacyl CoA racemase (AMACR) (Zehentner et al., 2006; Zielie et al., 2004) in prostate cancer cells found in bodily fluids such as serum and urine (Groskopf et al., 2006; Wright and Lange, 2007). Although these biomarkers may give increased specificity due to overexpression in prostate cancer cells (e.g., PCA3 expression is increased 60- to 100-fold in prostate cancer cells), a digital rectal examination is required to milk prostate cells into the urine just before specimen collection (Nakanishi et al., 2008). Such rectal examinations have inherent disadvantages such as the bias on collecting those cancer cells that are easily milked into urine and the involvement of medical doctors which is costly and time consuming.

[00138] Here, a new method of detecting the genetic profiles of these biomarkers is proposed to overcome the limitation mentioned above. The method comprises the steps of isolating exosomes from a bodily fluid and analyzing the nucleic acid from said exosomes. The procedures of the method are similar to those detailed in Example 9. In this example, the

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2017272272 07 Dec 2017 urine samples were from four diagnosed prostate cancer patients. As shown in FIG. 15c, the cancer stages were characterized in terms of grade, Gleason stage and PSA levels. In addition, the nucleic acids analyzed by nested-RT-PCR as detailed in Example 7 were TMPRSS2-ERG and PCA3, two of the newly identified biomarkers of prostate cancer. For amplification of TMPRSS2-ERG, the primer pair for the first amplification step was TMPRSS2-ERG FI (SEQ ID NO: 47) and TMPRSS2-ERG RI (SEQ ID NO: 48); and the primer pair for the second amplification step was TMPRSS2-ERG F2 (SEQ ID NO: 49) and TMPRSS2-ERG R2 (SEQ ID NO: 50). The expected amplicon is 122 base pairs (bp) and gives two fragments (one is 68 bp, the other is 54 bp) after digestion with the restriction enzyme Haell. For amplification of PCA3, the primer pair for the first amplification step was PCA3 FI (SEQ ID NO: 51) and PCA3 RI (SEQ ID NO: 52); and the primer pair for the second amplification step was PCA3 F2 (SEQ ID NO: 53) and PCA3 R2 (SEQ ID NO: 54). The expected amplicon is 152 bp in length and gives two fragments (one is 90 bp, the other is 62 bp) after digestion with the restriction enzyme Seal.

[00139] As shown in FIG. 15a, in both patient 1 and 2, but not in patient 3 and 4, the expected amplicon of TMPRSS2-ERG could be detected and digested into two fragments of expected sizes. As shown in FIG. 15b, in all four patients, the expected amplicon of PCA3 could be detected and digested into two fragments of expected sizes. Therefore, PCA3 expression could be detected in urine samples from all four patients, while TMPRSS2-ERG expression could only be detected in urine samples from patient 1 and 2 (FIG. 15c). These data, although not conclusive due to the small sample size, demonstrate the applicability of the new method in detecting biomarkers of prostate cancer. Further, the exosome method is not limited to diagnosis but can be employed for prognosis and/or monitoring other medical conditions related to prostate cancer.

Example 13: Microvesicles in non-invasive prenatal diagnosis [00140] Prenatal diagnosis is now part of established obstetric practice all over the world. Conventional methods of obtaining fetal tissues for genetic analysis includes amniocentesis and chorionic villus sampling, both of which are invasive and confer risk to the unborn fetus. There is a long-felt need in clinical genetics to develop methods of noninvasive diagnosis. One approach that has been investigated extensively is based on the discovery of circulating fetal cells in maternal plasma. However, there are a number of barriers that hinder its application in clinical settings. Such barriers include the scarcity of fetal cells (only 1.2 cells/ml maternal blood), which requires relatively large volume blood

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2017272272 07 Dec 2017 samples, and the long half life of residual fetal cells from previous pregnancy, which may cause false positives. Another approach is based on the discovery of fetal DNA in maternal plasma. Sufficient fetal DNA amounts and short clearance time overcome the barriers associated with the fetal cell method. Nevertheless, DNA only confers inheritable genetic and some epigenetic information, both of which may not represent the dynamic gene expression profiles that are linked to fetal medical conditions. The discovery of circulating fetal RNA in maternal plasma (Ng et al., 2003b; Wong et al., 2005) may be the method of choice for non-invasive prenatal diagnosis.

[00141] Several studies suggest that fetal RNAs are of high diagnostic value. For example, elevated expression of fetal corticotropin-releasing hormone (CRH) transcript is associated with pre-eclampsia (a clinical condition manifested by hypertension, edema and proteinuria) during pregnancy (Ng et al., 2003a). In addition, the placenta-specific 4 (PLAC4) mRNA in maternal plasma was successfully used in a non-invasive test for aneuploid pregnancy (such as trisomy 21, Down syndrome) (Lo et al., 2007). Furthermore, fetal human chorionic gonadotropin (hCG) transcript in maternal plasma may be a marker of gestational trophoblastic diseases (GTDs), which is a tumorous growth of fetal tissues in a maternal host. Circulating fetal RNAs are mainly of placenta origin (Ng et al., 2003b). These fetal RNAs can be detected as early as the 4th week of gestation and such RNA is cleared rapidly postpartum.

[00142] Prenatal diagnosis using circulating fetal RNAs in maternal plasma, nevertheless, has several limitations. The first limitation is that circulating fetal RNA is mixed with circulating maternal RNA and is not effectively separable. Currently, fetal transcripts are identified, based on an assumption, as those that are detected in pregnant women antepartum as well as in their infant’s cord blood, yet are significantly reduced or absent in maternal blood within 24 or 36 hours postpartum (Maron et al., 2007). The second limitation is that no method is established to enrich the circulating fetal RNA for enhanced diagnostic sensitivity since it is still unknown how fetal RNA is packaged and released. The way to overcome these limitations may lie in the isolation of microvesicles and the analysis of the fetal RNAs therein.

[00143] Several facts suggest that microvesicles, which are shed by eukaryotic cells, are the vehicles for circulating fetal RNAs in maternal plasma. First, circulating RNAs within microvesicles are protected from RNase degradation. Second, circulating fetal RNAs have been shown to remain in the non-cellular fraction of maternal plasma, which is consistent

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2017272272 07 Dec 2017 with the notion that microvesicles encompassing these fetal RNAs are able to be filtered through 0.22 um membrane. Third, similar to tumorous tissues which are know to shed micro vesicles, placental cells, which are a pseudo-malignant fetal tissue, are most likely capable of shedding micro vesicles. Thus, a novel method of non-invasive prenatal diagnosis is comprised of isolating fetal microvesicles from maternal blood plasma and then analyzing the nucleic acids within the microvesicles for any genetic variants associated with certain diseases and/or other medical conditions.

[00144] A hypothetical case of non-invasive prenatal diagnosis is as follows: peripheral blood samples are collected from pregnant women and undergo magnetic activated cell sorting (MACS) or other affinity purification to isolate and enrich fetus-specific micro vesicles. The microvesicular pellet is resuspended in PBS and used immediately or stored at -20°C for further processing. RNA is extracted from the isolated microvesicles using the Qiagen RNA extraction kit as per the manufacturer’s instructions. RNA content is analyzed for the expression level of fetal human chorionic gonadotropin (hCG) transcript.

An increased expression level of hCG compared to the standard range points to the development of gestational trophoblastic diseases (GTDs) and entail further the need for clinical treatment for this abnormal growth in the fetus. The sensitivity of micro vesicle technology makes it possible to detect the GTDs at a very early stage before any symptomatic manifestation or structural changes become detectable under ultrasonic examination. The standard range of hCG transcript levels may be determined by examining a statistically significant number of circulating fetal RNA samples from normal pregnancies.

[00145] This prenatal diagnostic method may be extrapolated to the prenatal diagnosis and/or monitoring of other diseases or medical conditions by examining those transcripts associated with these diseases or medical conditions. For example, extraction and analysis of anaplastic lymphoma kinase (ALK) nucleic acid from microvesicles of fetus origin from maternal blood is a non-invasive prenatal diagnosis of neuroblastoma, which is closely associated with mutations within the kinase domain or elevated expression of ALK (Mosse et al., 2008). Accordingly, the microvesicle methods and technology described herein may lead to a new era of much-needed, non-invasive prenatal genetic diagnosis.

Example 14: Melanoma diagnosis

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2017272272 07 Dec 2017 [00146] Melanoma is a malignant tumor of melanocytes (pigment cells) and is found predominantly in skin. It is a serious form of skin cancer and accounts for 75 percent of all deaths associated with skin cancer. Somatic activating mutations (e.g. V600E) of BRAF are the earliest and most common genetic abnormality detected in the genesis of human melanoma. Activated BRAF promotes melanoma cell cycle progression and/or survival.

[00147] Currently, the diagnosis of melanoma is made on the basis of physical examination and excisional biopsy. However, a biopsy can sample only a limited number of foci within the lesion and may give false positives or false negatives. The exosome method provides a more accurate means for diagnosing melanoma. As discussed above, the method is comprised of the steps of isolating exosomes from a bodily fluid of a subject and analyzing the nucleic acid from said exosomes.

[00148] To determine whether exosomes shed by melanoma cells contain BRAF mRNA, we cultured primary melanoma cells in DMEM media supplemented with exosome-depleted FBS and harvested the exosomes in the media using a similar procedure as detailed in Example 2. The primary cell lines were Yumel and M34. The Yumel cells do not have the V600E mutation in BRAF, while M34 cells have the V600E mutation in BRAF. RNAs were extracted from the exosomes and then analyzed for the presence of BRAF mRNA by RTPCR. The primers used for PCR amplification were: BRAF forward (SEQ ID NO: 55) and BRAF reverse (SEQ ID NO: 56). The amplicon is 118 base pairs (bp) long and covers the part of BRAF cDNA sequence where the V600E mutation is located. As shown in FIG. 16a, a band of 118 bp was detected in exosomes from primary melanoma cells (Yumel and M34 cells), but not in exosomes from human fibroblast cells or negative controls. The negative detection of a band of 118 bp PCR product is not due to a mistaken RNA extraction since GAPDH transcripts could be detected in exosomes from both melanoma cell and human fibroblast cells (FIG. 16b). The 118 bp PCR products were further sequenced to detect the V600E mutation. As shown in FIGS. 16c and 16d, PCR products from YUMEL cells, as expected, contain wild type BRAF mRNA. In contrast, PCR products from M34 cells, as expected, contain mutant BRAF mRNA with a T-A point mutation, which causes the amino acid Valine (V) to be replaced by Glutamic acid (E) at the amino acid position 600 of the BRAF protein. Furthermore, BRAF mRNA cannot be detected in exosomes from normal human fibroblast cells, suggesting the BRAF mRNA is not contained in exosomes of all tissue origins.

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2017272272 07 Dec 2017 [00149] These data suggest that melanoma cells shed exosomes into the blood circulation and thus melanoma can be diagnosed by isolating these exosomes from blood serum and analyzing the nucleic acid therefrom for the presence or absence of mutations (e.g., V600E) in BRAF. The method described above can also be employed to diagnose melanomas that are associated with other BRAF mutations and mutations in other genes. The method can also be employed to diagnose melanomas that are associated with the expression profiles of BRAF and other nucleic acids.

Example 15: Detection of MMP levels from exosomes to monitor post transplantation conditions.

[00150] Organ transplants are usually effective treatments for organ failures. Kidney failure, heart disease, end-stage lung disease and cirrhosis of the liver are all conditions that can be effectively treated by a transplant. However, organ rejections caused by posttransplantation complications are major obstacles for long-term survival of the allograft recipients. For example, in lung transplantations, bronchiolitis obliterans syndrome is a severe complication affecting survival rates. In kidney transplants, chronic allograft nephropathy remains one of the major causes of renal allograft failure. Ischemia-reperfusion injury damages the donor heart after heart transplantation, as well as the donor liver after orthotopic liver transplantation. These post-transplantation complications may be ameliorated once detected at early stages. Therefore, it is essential to monitor posttransplantation conditions in order to alleviate adverse complications.

[00151] Alterations in the extracellular matrix contribute to the interstitial remodeling in post-transplantation complications. Matrix metalloproteinases (MMPs) are involved in both the turnover and degradation of extracellular matrix (ECM) proteins. MMPs are a family of proteolytic, zinc-dependent enzymes, with 27 members described to date, displaying multidomain structures and substrate specificities, and functioning in the processing, activation, or deactivation of a variety of soluble factors. Serum MMP levels may indicate the status of post-transplantation conditions. Indeed, circulating MMP-2 is associated with cystatin C, post-transplant duration, and diabetes mellitus in kidney transplant recipients (Chang et al., 2008). Disproportional expression of MMP-9 is linked to the development of bronchiolitis obliterans syndrome after lung transplantation (Hubner et al., 2005).

[00152] MMP mRNAs (MMP1, 8, 12, 15, 20, 21, 24, 26 and 27) can be detected in exosomes shed by glioblastoma cells as shown in Example 4 and Table 10. The present

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2017272272 07 Dec 2017 exosome method, isolating exosomes from a bodily fluid and analyzing nucleic acids from said exosomes, can be used to monitor transplantation conditions. The exosome isolation procedure is similar to that detailed in Example 2. The present procedures to analyze nucleic acid contained within exosomes are detailed in Example 9. A significant increase in the expression level of MMP-2 after kidney transplantation will indicate the onset and/or deterioration of post-transplantation complications. Similarly, a significantly elevated level of MMP-9 after lung transplantation, suggests the onset and/or deterioration of bronchiolitis obliterans syndrome.

[00153] Therefore, the exosome method can be used to monitor post-transplantation conditions by determining the expression levels of MMP proteins associated with posttransplantation complications. It is also expected that the method can be extrapolated to monitor post-transplantation conditions by determining the expression of other marker genes as well as monitor other medical conditions by determining the genetic profile of nucleic acids associated with these medical conditions.

Examples 16-18. Micro vesicles can be therapeutic agents or delivery vehicles of therapeutic agents.

Example 16: Micro vesicle proteins induce angiogenesis in vitro.

[00154] A study was designed and carried out to demonstrate glioblastoma microvesicles contribute to angiogenesis. HBMVECs (30,000 cells), a brain endothelial cell line, (Cell Systems, Catalogue #ACBRI-376, Kirkland, WA, USA) were cultured on Matrigel-coated wells in a 24-well plate in basal medium only (EBM) (Lonza Biologies Inc., Portsmouth, NH, USA), basal medium supplemented with glioblastoma microvesicles (EBM+ MV) (7 pg/well), or basal medium supplemented with a cocktail of angiogenic factors (EGM; hydrocortisone, EGF, FGF, VEGF, IGF, ascorbic acid, FBS, and heparin; Singlequots (EBM positive control). Tubule formation was measured after 16 hours and analyzed with the Image J software. HBMVECs cultured in the presence of glioblastoma microvesicles demonstrated a doubling of tubule length within 1 6 hours. The result was comparable to the result obtained with HBMCECs cultured in the presence of angiogenic factors (FIG. 18a). These results show that glioblastoma-derived microvesicles play a role in initiating angiogenesis in brain endothelial cells.

[00155] Levels of angiogenic proteins in microvesicles were also analyzed and compared with levels in glioblastoma donor cells. Using a human angiogenesis antibody

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2017272272 07 Dec 2017 array, we were able to detect 19 proteins involved in angiogenesis. Specifically, total protein from either primary glioblastoma cells or purified microvesicles isolated from said cells were lysed in lysis buffer (Promega, Madison, WI, USA) and added to the human angiogenesis antibody array (Panomics, Fremont CA, USA) according to manufacturer’s recommendations. The arrays were scanned and analyzed with the Image J software. As shown in FIG. 18b, of the seven of the 19 angiogenic proteins were readily detected in the microvesicles, 6 (angiogenin, IL-6, IL-8, TIMP-I, VEGF and TIMP-2) were present at higher levels on a total protein basis as compared to the glioblastoma cells (FIG. 18c). The three angiogenic proteins most enriched in microvesicles compared to tumor cells were angiogenin, IL-6 and IL-8, all of which have been implicated in glioma angiogenesis with higher levels associated with increased malignancy (25-27).

[00156] Microvesicles isolated from primary glioblastoma cells were also found to promote proliferation of a human U87 glioma cell line. In these studies, 100 000 U87 cells were seeded in wells of a 24-well plate and allowed to grow for three days (DMEM-5%FBS) or DMEM-5%FBS supplemented with 125 pg microvesicles isolated from primary glioblastoma cells. After three days, untreated U87 cells (FIG. 19a) were found to be fewer in number as determined using a Burker chamber, than those supplemented with microvesicles (FIG. 19b). Both non-supplemented and supplemented U87 cells had increased 5-and 8-fold in number over this period, respectively (FIG. 19c). Thus, glioblastoma micro vesicles appear to stimulate proliferation of other glioma cells.

Example 17: Glioblastoma micro vesicles are taken up by HBMVECs.

[00157] To demonstrate that glioblastoma microvesicles are able to be taken up by human brain microvesicular endothelial cells (HBMVECs), purified glioblastoma microvesicles were labeled with PKH67 Green Fluorescent labeling kit (Sigma-Aldrich, St Louis, MO, USA). The labeled microvesicles were incubated with HBMVEC in culture (5 pg/50,000 cells) for 20 min at 4°C. The cells were washed and incubated at 37°C for 1 hour. Within 30 min the PKH67-labeled microvesicles were internalized into endosome-like structures within the HBMVECs (FIG. 17a). These results show that glioblastoma micro vesicles can be internalized by brain endothelial cells.

[00158] Similar results were obtained when adding the fluorescently labeled micro vesicles to primary glioblastoma cells.

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Example 18: mRNA delivered by glioblastoma microvesicles can be translated in recipient cells.

[00159] To determine whether glioblastoma-derived microvesicles mRNA could be delivered to and expressed in recipient cells, primary human glioblastoma cells were infected with a self-inactivating lentivirus vector expressing secreted Gaussia luciferase (Glue) using a CMV promoter at an infection efficiency of >95%. The cells were stably transduced and generated microvesicles during the subsequent passages (2-10 passages were analyzed). Microvesicles were isolated from the cells and purified as described above. RT-PCR analysis showed that the mRNA for Glue (555 bp) as well as GAPDH (226 bp) were present in the microvesicles (FIG. 17b). The level of Glue mRNA was even higher than that for GAPDH as evaluated with quantitative RT-PCR.

[00160] Fifty micrograms of the purified microvesicles were added to 50,000 HBMVE cells and incubated for 24 hrs. The Glue activity in the supernatant was measured directly after micro vesicle addition (0 hrs), and after 15 hrs and 24 hrs. The Glue activity in the supernatant was normalized to the Glue protein activity associated with the micro vesicles.

The results are presented as the mean + SEM (n=4). Specifically, the activity in the recipient HBMVE cells demonstrated a continual translation of the microvesicular Glue mRNA. Thus, mRNA incorporated into the tumor microvesicles can be delivered into recipient cells and generate a functional protein.

[00161] The statistical analyses in all examples were performed using the Student's ttest.

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67. Parsons, D.W., S. Jones, X. Zhang, J.C. Lin, R.J. Leary, P. Angenendt, P. Mankoo, H. Carter, I.M. Siu, G.L. Gallia, A. Olivi, R. McLendon, B.A. Rasheed, S. Keir, T. Nikolskaya, Y. Nikolsky, D.A. Busam, H. Tekleab, L.A. Diaz, Jr., J. Hartigan, D.R. Smith, R.L. Strausberg, S.K. Marie, S.M. Shinjo, H. Yan, G.J. Riggins, D.D. Bigner,

R. Karchin, N. Papadopoulos, G. Parmigiani, B. Vogelstein, V.E. Velculescu, and

K.W. Kinzler. 2008. An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science.

68. Pelloski, C.E., K.V. Ballman, A.F. Furth, L. Zhang, E. Lin, E.P. Sulman, K. Bhat,

J.M. McDonald, W.K. Yung, H. Colman, S.Y. Woo, A.B. Heimberger, D. Suki, M.D. Prados, S.M. Chang, F.G. Barker, 2nd, J.C. Buckner, C.D. James, and K. Aldape. 2007. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. 25:2288-94.

69. Raposo, G., H.W. Nijman, W. Stoorvogel, R. Liejendekker, C.V. Harding, C.J. Melief, and H.J. Geuze. 1996. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 183:1161-72.

70. Roe, M.A., C. Spinks, A.L. Heath, L.J. Harvey, R. Foxall, J. Wimperis, C. Wolf, and

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71. Schetter, A.J., S.Y. Leung, J.J. Sohn, K.A. Zanetti, E.D. Bowman, N. Yanaihara, S.T. Yuen, T.L. Chan, D.L. Kwong, G.K. Au, C.G. Liu, G.A. Calin, C.M. Croce, and C.C. Harris. 2008. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 299:425-36.

72. Singer, C.F., D. Gschwantler-Kaulich, A. Fink-Retter, C. Haas, G. Hudelist, K. Czerwenka, and E. Kubista. 2007. Differential gene expression profile in breast cancer-derived stromal fibroblasts. Breast Cancer Res Treat.

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85. Wong, B.C., R.W. Chiu, N.B. Tsui, K.C. Chan, L.W. Chan, T.K. Lau, T.N. Leung, and Y.M. Lo. 2005. Circulating placental RNA in maternal plasma is associated with a preponderance of 5' mRNA fragments: implications for noninvasive prenatal diagnosis and monitoring. Clin Chem. 51:1786-95.

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89. Zielie, P.J., J.A. Mobley, R.G. Ebb, Z. Jiang, R.D. Blute, and S.M. Ho. 2004. A novel diagnostic test for prostate cancer emerges from the determination of alphamethylacyl-coenzyme a racemase in prostatic secretions. J Urol. 172:1130-3.

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Table 1. RNA in glioblastoma microvesicles can be used as sensitive biomarkers.

Nested RT-PCR was used to monitor EGFRvIII mRNA in glioma biopsy tissue as well as exosomes purified from a frozen serum sample from the same patient. Samples from 30 patients were analysed in a blinded fashion and PCR reactions were repeated at least three times for each sample. No EGFRvIII mRNA was found in serum microvesicles from 30 normal controls. PP1 refers to primer pair composed of SEQ ID NOs: 13 and 14. PP2 refers to primer pair composed of SEQ ID NOS: 15 and 16. refers to “not available”.

Patient#	Time of serum collection*	Serum volume	Biopsy EGFRvIII	Serum exosome EGFRvll l(PPl)	Serum exosome EGFRvlll(PP2)
1	0	3 ml	Yes	Yes	-
2	0	2 ml	No	No	-
3	0	2.5 ml	No	No	-
4	0	1 ml	Yes	No	Yes
5	0	1 ml	Yes	No	Yes
6	0	1 ml	No	No	-
7	0	0.6 ml	Yes	Yes	-
8	0	1 ml	No	No	-
9	0	1 ml	Yes	Yes	-
10	0	1 ml	No	Yes	-
11	0	2 ml	Yes	No	Yes
12	0	2 ml	Yes	Yes	-
13	0	2 ml	No	Yes	-
14	0	2 ml	Yes	Yes	-
15	0	2 ml	No	No	-
16	0	2 ml	No	No	-
17	0	1 ml	Yes	No	-
18	0	0.8 ml	Yes	No	-
19	0	1 ml	No	No	-
20	0	1 ml	No	No	-
21	0	1 ml	No	No	-
22	0	1 ml	No	No	-
23	0	1 ml	No	No	-
24	0	1 ml	No	No	-
25	0	1 ml	No	No	-
26	14	0.6 ml	Yes	No	Yes
27	14	1.2 ml	No	No	No
28	14	0.8 ml	Yes	No	Yes
29	14	0.9 ml	Yes	No	No
30	14	0.6 ml	Yes	No	Yes

''Days post-surgery of tumor removal

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Table 2 Abbreviations used in Table 3.

Abbreviation

A

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AL

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ALL

AML

AML*

APL

B-ALL

B-CLL

B-NHL

CLL

CML

CMML

CNS

D

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Dom

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L

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Mis

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MM

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N

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NK/T

NSCLC

O

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T-ALL

T-CLL

TGCT

T-PLL

Term amplification acute eosinophilic leukemia acute leukemia anaplastic large-cell lymphoma acute lymphocytic leukemia acute myelogenous leukemia acute myelogenous leukemia (primarily treatment associated) acute promyelocytic leukemia

B-cell acute lymphocyte leukemia

B-cell Lymphocytic leukemia

B-cell Non-Hodgkin Lymphoma chronic lymphatic leukemia chronic myeloid leukemia chronic myelomonocytic leukemia central nervous system large deletion dermatfibrosarcoma protuberans diffuse large B-cell lymphoma diffuse large-cell lymphoma dominant epithelial frames gastrointestinal stromal tumour juvenile myelomonocytic leukemia leukaemia/lymphoma mesenchymal mucosa-associated lymphoid tissue lymphoma myelodysplastic syndrome

Missense mediastinal large cell lymphoma with sclerosis multiple myeloma

Myeloproliferative disorder nonsense non-Hodgkin lymphoma natural killer T cell non small cell lung cancer other primary mediastinal B-cell lymphoma pre-B-cell acute lymphablastic leukaemia reccesive splice site translocation

T-cell acute lymphoblastic leukemia

T-cell chronic lymphocytic leukaemia testicular germ cell tumour

T cell prolymphocytic leukaemia

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2017272272 07 Dec 2017

Table 4: Commonly Upregulated Genes in Cancers
'Ο». , JnlGene	Gene symbol	N	Up#	Down #	UniGene	Gene symbol	N	Up#	Down #
5 is. 159430	FNDC3B	11	10	0	Hs. 239388	PAQR8	8	5	1
is. 518201	DTX3L	8	7	0	Hs. 592827	RBAK	8	5	1
} is. 530899	LOCI 62073	8	7	0	Hs. 525157	TNFSF13B	8	5	1
) is. 15159	CKLF	11	9	1	Hs. 126774	DTL	13	8	0
\ is. 474150	BID	16	13	0	Hs. 385913	ANP32E	13	8	1
Ί is. 7753	CALU	15	12	0	Hs. 532968	DKFP762E1312	13	8	1
- is. 418795	GLT2SDI	10	8	0	Hs. 372429	PDIA6	13	8	1
} is 435556	BFAR	12	9	0	Hs. 233952	PSMA7	13	8	1
is. 459362	PACI	12	9	1	Hs. 533770	SLC38A1	13	8	1
is. 521800	Cborf76	8	6	0	Hs. 489284	ARPC18	18	11	0
1 is. 209561	KIAA1715	8	6	0	Hs. 497788	EPRS	18	11	0
’ is. 585011	Clorf96	8	6	1	Hs. 79110	NCL	18	11	0
j is. .403933	FBX032	8	6	1	Hs. 251531	PSMA4	18	11	0
j is. 368853	AYTL2	15	11	1	Hs. 429180	Elf2S2	18	11	1
is. 511093	NUSAP1	11	8	0	Hs. 46S885	ILF3	18	11	1
1 is. 370895	RPN2	14	10	0	Hs. 169840	TTK	18	11	1
(J is. 180062	PSMBB	17	12	0	Hs. 489365	APIST	15	9	1
H is. 444600	BOLAZ	10	7	0	Hs. 256639	PPIH	15	9	1
s, is. 445890	CHIH4	13	9	0	Hs. 14559	CEP55	10	6	1
1 is. 534392	KDELR3	13	9	0	Hs. 308613	MTERFD1	10	6	1
Ί is. 632 191	ΧΤΡ3ΤΡΑ	13	9	0	Hs. 21331	ZW1LCH	10	6	1
is. 387567	ACLV	19	13	1	Hs. 524S99	NAPIL!	17	10	1
is. 533282	NONO	18	12	0	Hs. 78171	PGKI	17	10	2
is. 83753	SNRPB	18	12	0	Hs. 512380	PLEKHB2	12	7	1
is. 471441	PSMBZ	18	12	1	Hs. 352018	TAPI	19	11	1
is. 482497	TNPOI	18	12	1	Hs. 194698	CCNB2	14	8	1
is. 370937	TAPBP	15	10	0	Hs. 153357	PLOD3	14	8	1
is .126941	FAM49B	12	8	0	Hs. 471200	NRP2	14	8	2
is. 408629	KDELCI	12	8	0	Hs. 250822	AURKA	16	9	1
is. 497384	IPO9	12	8	1	Hs. 75528	GN12	16	9	1
is. 8752	TMEM4	12	8	1	Hs. 1197	HSPEI	16	9	1
is. 195642	C17orf27	9	6	0	Hs. 202672	DNMTI	18	10	1
is. 358997	TTL	9	6	0	Hs. 433670	FTL	18	10	1
is. 1600	CCT5	20	13	0	Hs. 519972	HLA-F	18	10	1
is. 269408	E2F3	17	11	0	HS. 520210	KDELR2	18	10	1
is. 234027	ZBTB12	17	11	1	Hs. 40515.1	CARD-4	11	6	1
is. 520205	EIF2AK1	14	9	0	Hs. 477700	DBRI	11	6	1
is. 89545	PSMB4	14	9	0	Hs. 14468	FLJ11286	11	6	1
is. 449415	EIF2C2	14	9	1	Hs. 516077	FLJ14668	11	6	1
is. 409065	FEN1	14	9	1	HS. 494337	GOLPH2	11	6	1
is. 313	SPP1	14	9	2	Hs.. 371036	ΝΟΧ4	11	6	1
is. .525135	FARP1	14	9	2	Hs. .438683	SLAMF8	11	6	1
Hs. 524390	K-ALPHA-1	11	7	0	Hs. 520714	SNXIO	11	6	1
Hs. .432360	SCNM1	11	7	0	Hs. 159428	BAX	13	7	1
Hs. 172028	ADAM 10	19	12	0	Hs. .311609	DDX39	13	7	1
Hs. 381189	CBX3	19	12	0	Hs. 463035	FKBP10	13	7	1
Hs. 522257	HNRPK	19	12	0	Hs. 438695	FKBP11	13	7	1
Hs. 470943	STATI	19	12	0	Hs. 515255	LSM4	13	7	1
Hs. 118638	NME1	19	12	1	Hs. 55285	MORC2	13	7	1
Hs. 519452	NPM1	19	12	1	Hs. 43666	PTP4A3	13	7	1
Hs. 506748	HDGF	16	10	0	Hs. 369440	SFXN1	13	7	1
Hs. 386283	ADAM 12	16	10	2	Hs. 517155	TMEPAI	13	7	1
Hs. 474740	APOL2	8	5	0	Hs. 631580	UBA2	13	7	1
Hs. 552608	Clorf58	8	5	0	Hs. 46346S	UTP16	13	7	1
Hs. 470654	CDCA7	8	5	0	Hs. 492974	WISP1	13	7	1
Hs. 17938	FMNL3	8	5	0	Hs. 113876	WHSC1	13	7	1
Hs. 143618	GEMIN6	8	5	0	Hs. 494614	BAT2D1	15	8	2
Hs. 6459	GPRI72A	8	5	0	Hs. 166463	HNRPU	19	10	2
Hs. 133294	IQGAP3	8	5	0

No number of studies (types of cancer) which have available expression data on a test gene.

Up # or down # number of cancer types whose expression of the tested gene is up or down -regulated. All these genes are significantly consistently up-regulated (P<10) in a large majority of cancer types, doi: 10.137/journalpone. 0001149.001

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Atty. Docket No. 030258-61532

Table 5: Commonly Downregulated Genes in Cancers
UnlGene	Gene symbol	N	Up#	Down #	UniGene	Gene symbol	N	Up#	Down #
Hs. 401835	TCEA12	10	0	8	Hs. 306083	LOC91689	8	0	5
Hs. 58351	ABCA8	13	0	10	Hs. 160953	PS3AIP1	8	0	5
Hs. 525205	NDRG2	12	0	9	Hs. 2112252	SLC24A3	8	0	5
Hs. 524085	USP2	12	0	9	Hs. 163079	TUBAL3	8	0	5
Hs. 172755	BRP44L	11	0	8	Hs. 389171	PINK1	13	0	8
Hs. 22242	ECHDC3	11	0	8	Hs. 470887	GULP1	13	1	8
Hs. 196952	HLF	19	1	13	Hs. 490981	MSRA	13	1	8
Hs. 496587	CHRDL1	12	0	8	Hs. 476092	CEEC3B	18	0	11
Hs. 476319	ECHDC2	12	0	8	Hs. 386502	EMO4	18	0	11
Hs. 409352	FLJ20701	12	0	8	Hs. 137367	ANK2	18	1	11
Hs. 103253	PLIN	12	0	8	Hs. 212088	ΕΡΗΧ2	18	1	11
Hs. 293970	ALDH6A1	18	1	12	Hs. 157818	KCNAB1	18	1	11
Hs. 390729	ERBB4	17	0	11	Hs. 163924	NR3C2	18	1	11
Hs. 553502	RORA	17	0	11	Hs. 269128	PPP2R1B	18	1	11
Hs. 388918	RECK	14	0	9	Hs. 40582	CDC148	15	1	9
Hs. 216226	SYNGR1	14	0	9	Hs. 438867	FL20489	10	1	6
Hs. 506357	faml07a	14	1	9	Hs. 224008	FEZ1	17	1	10
Hs. 476454	ABHD6	11	0	7	Hs. 443789	C6orf60	12	1	7
Hs. 519694	Csorf4	11	0	7	Hs. 475319	LRRFIP2	12	1	7
Hs. 528385	DHR54	11	0	7	Hs. 514713	MPPE1	12	1	7
Hs. 477288	TRPM3	1	0	7	Hs. 183153	ARL4D	19	1	11
Hs. 420830	HIF3A	11	1	7	Hs. 642660	C10orflll6	19	1	11
Hs. 511265	SEMA6D	11	1	7	Hs. 495912	DMD	19	1	11
Hs. 436657	CLU	19	1	12	Hs. 503126	SHANK2	14	1	8
Hs. 78482	PALM	16	0	10	Hs. 481342	SORBS2	14	1	8
Hs. 82318	WASF3	16	0	10	Hs. 169441	MAGI1	16	1	9
Hs. 268869	ADHFE1	8	0	5	Hs. 75652	GSTM5	18	1	10
Hs. 34494	AGXT2	8	0	5	Hs. 405156	PPAP28	18	1	10
Hs. 249129	CIDEA	8	0	5	Hs. 271771	SNCA	18	1	10
Hs. 302754	EFCBP1	8	0	5	Hs. 181855	CASC5	9	1	5
Hs. 521953	EFHC2	8	0	5	Hs. 506458	ANKS1B	11	1	6
Hs. 200100	Ellsl	8	0	5	Hs. 445885	KIAA1217	11	1	6
Hs. 479703	FL21511	8	0	5	Hs. 643583	DKFZp667G2110	13	1	7
Hs.. 500750	HPSE2	8	0	5	Hs. 406787	FBX03	13	1	7
Hs. 380929	LDHD	8	0	5	Hs. 431498	FOXP1	13	1	7

All these genes are significantly consistently down-regulated (P < 10 4 in a large majority of cancer types, doi :10.1371/j ournal.pone.0001149. t002

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Table 6: Commonly Upregulated Genes in Pancreatic Cancer
Accession	Gene Symbol	Gene Name	FC
NM 006475	POSTN	periostin, osteoblast specific factor	13.28
NM 005980	SI OOP	S100 calcium binding protein P	12.36
NM 004385	CSPG2	chondroitin sulfate proteoglycan 2 (versican)	10.57
NM 003118	SPARC	secreted protein, acidic cysteine-rich (osteonectin)	10.46
NM 003225	TFF1	trefoil factor 1 (breast cancer, estrogen-inducible sequence expressed in)	8.13
NM 002026	FN1	fibronectin 1	7.93
NM 006142	SFN	strati fin	7.81
NM 000393	COL5A2	collagen, type V, alpha 2	7.22
NM 005940	MMP11	matrix metalloproteinase 11 (stromelysin 3)	7.17
NM 000088	COL1A1	collagen, type I, alpha 1	6.50
NM 000930	PLAT	plasminogen activator, tissue	6.46
NM 003064	SLPI	secretory leukocyte protease inhibitor (antileukoproteinase)	6.01
NM 006516	SLC2A1	solute carrier family 2 (facilitated glucose transporter), member 1	5.39
NM 003226	TFF3	trefoil factor 3 (intestinal)	5.28
NM 004460	FAP	fibroblast activation protein alpha	5.20
NM 003467	CXCR4	chemokine (C-X-C motif) receptor 4	5.18
NM 003247	THBS2	thrombospondin 2	5.04
NM 012101	TRIM29	tripartite motif-containing	4.91
NM 033664	CDH11	cadherin 11, type 2, OB-cadherin (osteoblast)	4.52
NM 006169	NNMT	nicotinamide N-methyltransferase	4.51
NM 004425	ECM1	extracellular matrix protein 1	4.39
NM 003358	UGCG	UDP-glucose ceramide glucosyltransferase	4.36
NM 000700	ANXA1	annexin Al	4.31
NM 004772	C5orfl3	chromosome 5 open reading frame 13	4.29
NM 182470	PKM2	pyruvate kinase, muscle	4.28
NM 004994	MMP9	matrix metalloproteinase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)	4.19
NM 006868	RAB31	RAB31, member RAS oncogene family	4.18
NM 001932	MPP3	membrane protein, palmitoylated 3 (MAGUK p55 subfamily member 3)	4.16
AF200348	D2S448	Melanoma associated gene	4.14
NM 000574	DAF	decay accelerating factor for complement (CD55, Cromer blood group system)	4.11
NM 000213	ITGB4	integrin beta	4.11
NM 001645	APOC1	apolipoprotein C-I	3.86
NM 198129	LAMA3	laminin, alpha 3	3.86
NM 002997	SDC1	syndecan 1	3.80
NM 001769	CD9	CD9 antigen (p24)	3.78
BC004376	ANXA8	annexim A8	3.74
NM 005620	S100A11	S100 calcium binding protein All (calgizzarin)	3.72
NM 002659	PLAUR	plasminogen activator urokinase receptor	3.70
NM 002966	S100A10	S100 calcium binding protein A10 (annexin II ligand, calpactin I, light polypeptide (pi 1))	3.67
NM 004898	CLOCK	clock homolog (mouse)	3.65
NM 002345	LUM	lumican	3.59
NM 006097	MYL9	myosin light polypeptide 9, regulatory	3.44
NM 004120	GBP2	guanylate binding protein 2, interferon-inducible	3.44
AK056875	LOC91316	similar to bK246H3.1 (immunoglobulin lambda-like polypeptide 1, pre-B-cell specific)	3.40
NM 001827	CKS2	CDC28 protein kinase requlatorv subunit 2	3.36
NM 002203	ITGA2	integrin alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)	3.35
NM 000599	IGFBP5	insulin-like growth factor binding protein 5	3.33
NM 004530	MMP2	matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)	3.33
NM 004335	BST2	bone marrow stromal cell antigen	3.30
NM 000593	TAPI	transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)	3.29
NM 004915	ABCG1	ATP-bindina cassette sub-familv G (WHITE), member	3.27
NM 001235	SERPINH 1	serine (or cysteine) proteinase inhibitor, clade H (heat shock protein 47), member 1 (collagen binding protein 1)	3.25
NM 001165	BIRC3	baculoviral IAP repeat-containing 3	3.23
NM 002658	PLAU	plasminogen activator, urokinase	3.20
NM 021103	TMSB10	thymosin, beta 10	3.18
NM 000304	PMP22	peripheral myelin protein 22	3.15
XM 371541	K1AA1641	KIAA1641 protein	3.11
NM 012329	MMD	monocyte to macrophage differentiation-associated	3.07
NM 182744	NBL1	neuroblastoma suppression of tumorigenicity 1	3.06
NM 002245	KCNK1	potassium channel, subfamily K, member 1	3.03
NM 000627	LTBP1	latent transforming growth factor beta binding protein 1	3.02
NM 000063	C2	complement component 2	3.01
NM 000100	CSTB	cystatin B (stefin B)	2.99
NM 000396	CTSK	cathepsin K (pycnodysostosis)	2.98

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NM 016816	OAS1	2' 5'-oliaoadenylate synthetase 1, 40/46kDa	2.98
NM 004240	TRIP 10	thyroid hormone receptor interactor 10	2.95
NM 000138	FBN1	fibrillin 1 (Marfan syndrome)	2.94
NM 002318	LOXL2	lysyl oxidase-like 2	2.92
NM 002053	GBP1	guanylate binding orotein 1 interferon-inducible, lysyl 67kDa	2.90
NM 005564	LCN2	lipocalin 2 (oncogene 24p3)	2.88
NM 153490	KRT13	keratin 13	2.85
NM 004723	ARHGEF 2	rho/rac guanine nucleotide exchange factor (GEF) 2	2.80
NM 004146	NDUFB7	NADH dehydrozenase (ubiquinone) 1 beta subcomplex, 7, 18kDa	2.79
NM 003937	KYNU	kynureninase (L-kynurenine hvdrolase)	2.77
NM 002574	PRDX1	Peroxiredoxin 1	2.77
NM 002444	MSN	moesin	2.73
NM 002901	RCN1	reticulocalbin 1, EF-hand calcium binding domain	2.73
NM 005165	ALDOC	aldolase C, fructose-bisphosphate	2.72
NM 002204	ITGA3	integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor)	2.72
NM 033138	CALD1	caldesmon 1	2.71
NM 003816	ADAM9	a disintegrin and metalloproteinase domain 9 (meltrin gamma)	2.69
NM 173843	IL1RN	interleukin 1 receptor antagonist	2.66
NM 000602	SERPINE 1	serine (or cysteine) proteinase inhibitor, clade E (nexin, plasminggen activator inhibitor type 1), member 1	2.65
NM 002213	ITGB5	integrin, beta 5	2.64
NM 004447	EPS 8	epidermal growth factor receptor pathway substrate 8	2.64
NM 002928	RGS16	regulator of G-protein singalling 16	2.62
NM 001288	CLIC1	chloride intracellular channel 1	2.61
NM 015996	TAGLN	transgelin	2.57
NM 002087	GRN	granulin	2.55
NM 001183	ATP6AP1	ATPase, H+ transporting, lysosomal accessory protein 1	2.54
NM 001730	KLF5	Kruppel-like factor 5 (intestinal)	2.51
NM 003516	HIST2H2 AA	histone 2, H2aa	2.50
NM 014736	KIAA0101	KIAA0101 gene product	2.49
NM 002290	LAMA4	laminin, alpha 4	2.49
NM 001826	CKS1B	CDC28 protein kinase reaulatory subunit IB	2.48
NM 001814	CTSC	cathepsin C	2.45
NM 176825	SULT1C1	sulfotransferase family cytosolic, 1C, member 1	2.43
NM 002862	PYGB	phosphorylase, glycogen; brain	2.41
NM 000917	P4HA1	procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4- hydroxylase), alpha polypeptidel	2.41
NM 001428	EN01	enolase 1 (alpha)	2.40
NM 001425	EMP3	epithelial membrane protein 3	2.40
NM 019111	HLA-DRA	maior histocompatibility complex, class II, DR alpha	2.38
NM 001387	DPYSL3	dihydropyrimidinase-like 3	2.36
NM 006471	MRCL3	myosin regulatory light chain MRCL3	2.34
NM 006332	IFI30	interferon gamma-inducible protein 30	2.34
NM 001312	CRIP2	cysteine-rich protein 2	2.33
NM 002224	ITPR3	inositol 1 4 5-triphosphate receptor tvpe 3	2.31
NM 053025	MYLK	myosin light peptide kinase	2.29
NM 002785	PSG11	pregnancy specific beta-1-glycoprotein 11	2.27
NM 000900	MGP	matrix Gia protein	2.26
NM 000962	PTGS1	prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxyenase)	2.25
NM 005915	MCM6	minichromosome maintenance deficient 6 (MIS5 homolog, S. pombe) (S. cerevisiae)	2.24
NM 001067	TOP2A	topoisomerase (DNA) II alpha 170kDa	2.23
NM 001878	CRABP2	cellular retinoic acid binding protein 2	2.23
NM 006745	SC4MOL	sterol-C4-methyl oxidase-like	2.22
NM 003528	HIST2H2	histone 2, H2be	2.22
BF347579		Transcribed sequence with strong similarity to protein pir:I38500 (H.sapiens) 138500 interferon gamma receptor accessory factor-1 precursor - human	2.21
NM 005261	GEM	GTP binding protein overexpressed in skeletal muscle	2.19
NM 021874	CDC25B	cell division cycle 25B	2.18
NM 022550	XRCC4	X-ray repair complementing defective repair in Chinese hamster cells 4	2.17
NM 020250	GSN	gelsolin (amyloidosis, Finnish type)	2.17
NM 002916	RFC4	replication factor C (activator 1) 4, 37kDa	2.16
NM 005606	LGMN	legumain	2.14
NM 006762	LAPTM5	Lysosomal-associated multispanning membrane protein-5	2.14
NM 002727	PRG1	proteoglycan 1, secretory granule	2.14
NM 002609	PDGFRB	platelet-derived growth factor receptor, beta polypeptide	2.14
NM 001424	EMP2	epithelial membrane protein 2	2.12
NM 005022	PFN1	profilin 1	2.12
NM 001657	AREG	amphiregulin amphireaulin (schwannoma-derived growth factor)	2.11
NM 005100	AKAP12	A kinase (PRKA) anchor protein (gravin) 12	2.11
NM 000860	HPGD	hydroxyprostaglandin dehydrogenase 15 (NAD)	2.10

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NM 007115	TNFAIP6	tumor necrosis factor alpha-induced protein 6	2.09
NM 021638	AFAP	actin filament associated protein	2.08
NM 001946	DUSP6	dual specificity phosphatase 6	2.05
NM 181802	UBE2C	ubiquitin-conjugating enzyme E2C	2.04
NM 002593	PCOLCE	procollagen C-endopeptidase enhancer	2.02
NM 033292	CASP1	caspase 1, apoptosis-related cysteine protease (interleukin 1, beta, convertase)	2.02
NM 003870	IQGAP1	IQ motif containing GTPase activating protein 1	2.02
NM 005563	STMN1	stathmin 1/oncoprotein 18	2.01
NM 005558	LAD1	ladinin 1	2.01
NM 001776	ENTPD1	ectonucleoside triphosphate diphosphohydrolase 1	2.00
NM 001299	CNN1	calponin 1, basic, smooth muscle	2.00
AK055128	PSMD14	proteasome (prosome, macropain) 26S subunit, non-ATPase, 14	2.00
NM 006304	SHFM1	split hand/foot malformation (ectrodactyly) type 1	1.98
NM 004024	ATF3	activating transcription factor 3	1.98
NM 000291	PGK1	phosphoglycerate kinase 1	1.98
NM 006520	TCTE1L	t-complex-associated-testis-expressed 1 -like	1.97
NM 201380	PLEC1	plectin 1 intermediate filament binding protein 500kDa	1.97
NM 002838	PTPRC	protein tyrosine phosphatase, receptor type, C	1.97
NM_000211	ITGB2	integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)	1.97
NM 002577	PAK2	p21 (CDKNlA)-activated kinase 2	1.96
NM 000295	SERPINA 1	serine (or cysteine) proteinase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1	1.96
NM 183001	SHC1	SHC (Src homology 2 domain containing) transforming protein 1	1.96
NM 005019	PDE1A	phosphodiesterase 1A, calmodulin-dependent	1.95
NM 002298	LCP1	lymphocyte cytosolic protein 1 (L-plastin)	1.95
NM 006769	LMO4	LIM domain only 4	1.94
NM 001465	FYB	FYN binding protein (FYB-120/130)	1.93
NM 183422	TSC22	transforming growth factor beta-stimulated protein TSC-22	1.92
NM 001777	CD47	CD47 antigen (Rh-related antigen, integrin-associated signal transducer )	1.92
NM 001755	CBFB	core-binding factor, beta subunit	1.90
NM 005544	IRS1	insulin receptor substrate 1	1.88
NM 000698	ALOX5	arachidonate 5-lipoxygenase	1.88
NM 006096	NDRG1	N-myc downstream regulated gene 1	1.88
NM 001105	ACVR1	activin A receptor, type 1	1.87
NM 003105	SORL1	sortilin-related receptor, L(DLR class) A repeats-containing	1.85
NM 001998	FBLN2	fibulin 2	1.85
NM 014791	MELK	maternal embryonic leucine zipper kinase	1.85
NM 003092	SNRPB2	small nuclear ribonucleoprotein polypeptide B	1.84
NM 001120	TETRAN	tetracycline transporter-like protein	1.84
NM 182943	PLOD2	procollagen-lysine, 2-oxoglutarate 5-dioxygenase (lysine hydroxylase) 2	1.83
NM 181862	BACH	brain acyl-CoA hydrolase	1.82
NM 021102	SPINT2	serine protease inhibitor, Kunitz type, 2	1.82
NM 004419	DUSP5	dual specificity phosphatase 5	1.81
NM 006482	DYRK2	dual specificity tyrosine-(Y)-phosphorylation regulated kinase 2	1.81
NM 145690	YWHAZ	tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide	1.81
NM 000714	BZRP	benzodiazapine receptor (peripheral)	1.81
NM 013995	LAMP2	lysosomal-associated membrane protein 2	1.80
CA45O153	ACYP1	acylphosphatase 1, erythrocyte (common) type	1.80
NM 000405	GM2A	GM2 ganglioside activator protein	1.79
NM 139275	AKAP1	A kinase (PRKA) anchor protein 1	1.79
NM 001679	ATP1B3	ATPase, Na+/K+ transporting, beta 3 polypeptide	1.79
NM 016343	CENPF	centromere protein F, 350/400ka (mitosin)	1.79
NM 002201	ISG20	interferon stimulated gene 20kDa	1.79
NM 002463	MX2	myxovirus (influenza virus) resistance 2 (mouse)	1.79
NM 006820	Clorf29	chromosome 1 open reading frame 29	1.79
NM 201397	GPX1	glutathione peroxidase 1	1.79
NM 005738	ARL4	ADP-ribosylation factor-like 4	1.78
NM 001038	SCNN1A	sodium channel nonvoltage-gated 1 alpha	1.78
NM 002863	PYGL	phosphorylase, glycogen; liver (Hers disease, glycogen storage disease type VI)	1.78
NM 001281	CKAP1	cytoskeleton associated protein 1	1.77
NM 003879	CFLAR	CASP8 and FADD-like apoptosis regulator	1.76
NM 182948	PRKACB	protein kinase, cAMP-dependent catalytic, beta	1.75
NM 006009	TUB A3	tubulin, alpha 3	1.75
NM 201444	DGKA	diacylglycerol kinase, alpha 80kDa	1.74
NM 005471	GNPDA1	glucosamine-6-phosphate deaminase 1	1.74
NM 001451	FOXF1	forkhead box FI	1.74
NM 001988	EVPL	envoplakin	1.73
NM 021724	NR1D1	nuclear receptor subfamily 1, group D member 1	1.73
NM 006364	SEC23A	Sec23 homolog A (S. cerevisiae)	1.72
NM 002129	HMGB2	high-mobility group box 2	1.72

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NM 004172	SLC1A3	solute carrier family 1 (glial high affinity glutamate transporter), member 3	1.71
NM 001421	ELF4	E74-like factor 4 (ets domain transcription factor)	1.71
NM 005566	LDHA	lactate dehydrogenase A	1.70
NM 000270	NP	nucleoside phosphorylase	1.69
NM 153425	TRADD	TNFRSFlA-associated via death domain	1.67
NM 004762	PSCD1	pleckstrin homology, Sec7 and coiled-coil domains (cytohesin 1)	1.67
NM 001985	ETFB	electron-transfer-flavoprotein, beta polypeptide	1.67
NM 016587	CBX3	chromobox homolog 3 (HP1 gamma homolog, Drosophila)	1.66
NM 002085	GPX4	glutathione peroxidase 4 (phospholipid hydroperoxidase)	1.66
NM 002795	PSMB3	proteasome (prosome, macropain) subunit, beta type, 3	1.65
NM 000963	PTGS2	prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclopxyoenase)	1.65
NM 001642	APLP2	amyloid beta (A4) precursor-like protein 2	1.65
NM 000569	FCGR3A	Fc fragment of lgG low affinity iiia receptor for (CD16)	1.64
NM 000362	TIMP3	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory)	1.63
NM 002417	MKI67	antigen identified by monoclonal antibody Ki-67	1.63
NM 000175	GPI	glucose phosophate isomerase	1.63
AF179995	SEPT8	septin 8	1.62
NM 004121	GGTLA1	gamma-glutamyltransferase-like activity 1	1.62
NM 002690	POLB	polymerase (DNA directed), beta	1.62
NM 004334	BST1	bone marrow stromal cell antigen 1	1.61
NM 001892	CSNK1A1	casein kinase 1, alpha 1	1.61
NM 014670	BZW1	basic leucine zipper and W2 domains 1	1.60
NM 001110	ADAM 10	a disintegrin and metalloproteinase domain 10	1.60
NM 005792	MPHOSP H6	M-phase phosphoprotein 6	1.60
NM 001126	ADSS	adenylosuccinate synthase	1.59
XM 376059	SERTAD2	SERTA domain containing 2	1.59
NM 001664	ARHA	ras homolog gene family, member A	1.59
NM 002475	MLC1SA	myosin light chain 1 slow a	1.59
NM 014498	GOLPH4	golgi phosphoprotein 4	1.59
NM 005964	MYH10	myosin heavy polypeptide 10 non-muscle	1.59
NM OO333O	TXNRD1	thioredoxin reductase 1	1.59
NM 001757	CBR1	carbonyl reductase 1	1.58
NM OO313O	SRI	sorcin	1.57
NM 006765	TUSC3	tumor suppressor candidate 3	1.57
NM 183047	PRKCBP1	protein kinase C binding protein 1	1.57
NM 005333	HCCS	holocytochrome c synthase (cytochrome c heme-lyase)	1.57
NM 001444	FABP5	fatty acid binding protein 5 (psoriasis-associated)	1.57
NM 001799	CDK7	cyclin-dependent kinase 7 (M015 homolog, Xenopus laevis, cdk-activating kinase)	1.57
NM 001539	DNAJA1	DnaJ (Hsp40) homolog subfamily A member 1	1.57
NM 004475	FLOT2	flotillin 2	1.57
NM 004308	ARHGAP1	Rho GTPase activating protein 1	1.56
NM 002388	MCM3	MCM3 minichromosome maintenance deficient 3 (S. cerevisiae)	1.56
NM 006435	ΙΕΕΓΜ2	interferon induced transmembrane protein 2 (1-8D)	1.56
NM 000454	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	1.56
NM 015161	ARL6IP	ADP-ribosylation factor-like 6 interacting protein	1.56
NM 078480	SIAHBP1	fuse-binding protein-interacting repressor	1.56
NM 025207	PP591	FAD-synthetase	1.56
NM 002833	PTPN9	protein tyrosine phosphatase non-receptor type 9	1.55
NM 001753	CAV1	caveolin 1 caveolae protein 22kDa	1.55
NM 003286	TOPI	topoisomerase (DNA) I	1.55
BU739663		Transcribed sequence with moderate similarity to protein sp:P13196 (H.sapiens) HEM1_HUMAN 5-aminolevulinic acid synthase, nonspecific mitochondrial precursor	1.55
NM 006788	RALBP1	ralA binding protein 1	1.54
NM 000944	PPP3CA	protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform (calcineurin A alpha)	1.54
NM 003374	VDAC1	voltaqe-dependent anion channel 1	1.54
NM 000560	CD53	CD53 antigen	1.54
NM 002037	FYN	FYN oncogene related to SRC FGR, YES	1.54
NM 002885	RAP1GA1	RAP1 GTPase activating protein 1	1.53
NM 018979	PRKWNK 1	lprotein kinase, lysine deficient 1	1.53
NM 002835	PTPN12	protein tyrosine phosphatase, non-receptor type 12	1.53
NM 007315	STAT1	signal transducer and activator of transcription 1, 91kDa	1.52
NM 014846	KIAA0196	KIAA0196 gene product	1.52
NM 001237	CCNA2	cyclin A2	1.52
NM 004596	SNRPA	small nuclear ribonucleoprotein polypeptide A	1.52
NM 002790	PSMA5	proteasome (prosome, macropoain) subunit, alpha type, 5	1.52
NM 015361	R3HDM	R3H domain (binds single-stranded nucleic acids) containing	1.52
NM 001665	ARHG	ras homolog gene family, member G (rho G)	1.51
NM 002788	PSMA3	proteasome (prosome macropain) subunit, alpha type, 3	1.50
NM 006904	PRKDC	protein kinase, DNA-activated, catalytic polypeptide	1.50
NM 003400	XPO1	exportin 1 (CRM1 homolog, yeast)	1.50

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NM 178014	OK/SW-cl.56	beta 5-tubulin	1.50
NM 002634	PHB	prohibitin	1.49
NM 004792	PPIG	peptidyl-prolyl isomerase G (eyclophilin G)	1.49
NM 002508	NID	nidogen (enactin)	1.49
NM 001765	CD1C	CD1C antigen, c polypeptide	1.48
NM_000311	PRNP	prion protein (p27-30) (Creutzfeld-Jakob disease, Gerstmann-Strausler-Scheinker syndrome, fatal familial insomnia)	1.48
NM 006437	ADPRTL1	ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)-like 1	1.48
NM 002759	PRKR	protein kinase, interferon-inducible double stranded RNA dependent	1.48
NM 014669	KIAA0095	KIAA0095 gene product	1.47
NM 003391	WNT2	wingless-type MMTV integration site family member 2	1.47
NM 004309	ARHGDIA	Rho GDP dissociation inhibitor (GDI) alpha	1.47
NM 000418	IL4R	interleukin 4 receptor	1.46
NM 003352	UBL1	ubiquitin-like 1 (sentrin)	1.46
NM 006290	TNFAIP3	tumor necrosis factor alpha-induced protein 3	1.45
NM 004763	ITGB1BP1	integrin beta 1 binding protein 1	1.45
NM 005754	G3BP	Ras-GTPase-activating protein SH3-domain-binding protein	1.45
NM 021990	GAB RE	gamma-aminobutyric acid (GABA) A receptor, epsilon	1.44
NM 001379	DNMT1	DNA (cytosine-5-)-methyltransferase 1	1.44
NM 001154	ANXA5	annexin A5	1.44
NM 004354	CCNG2	cyclin G2	1.44
NM 005002	NDUFA9	NADH dehydroaenase (ubiquinone) 1 alpha subcomplex, 9, 39kDa	1.43
NM 001931	DLAT	dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydroaenase complex)	1.43
NM 005902	MADH3	MAD mothers against decapentaplegic homolog 3 (Drosophila)	1.43
NM 000110	DPYD	dihydropyrimidine dehydrogenase	1.43
NM 001316	CSE1L	CSE1 chromosome segregation 1-like (yeast)	1.43
NM 000167	GK	glycerol kinase	1.43
NM 001924	GADD45 A	growth arrest and DNA-damage-inducible, alpha	1.42
NM 014225	PPP2R1A	protein phosphatase 2 (formerly 2A), regulatory subunit A (PR 65), alpha isoform	1.42
NM 001233	CAV2	caveolin 2	1.42
NM 176863	PSME3	proteasome (prosome, macropain) activator subunit 3 (PA28 gamma; Ki)	1.42
NM 001905	CTPS	CTP synthase	1.41
NM 005653	TFCP2	transcription factor CP2	1.41
NM 003405	YWHAH	tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide	1.41
NM 003392	WNT5A	wingless-type MMTV integration site family, member 5A	1.40
NM 002375	MAP4	microtubule-associated protein 4	1.40
NM 006353	HMGN4	high mobility qroup nueleosomal binding domain 4	1.39
NM 006527	SLBP	stem-loop (histone) bindino protein	1.39
NM 000517	HBA2	hemoglobin alpha 2	1.38
NM 002661	PLCG2	phospholipase C, gamma 2 (phosphatidylinositol-specific)	1.38
NM 001493	GDI1	GDP dissociation inhibitor 1	1.38
NM 181430	FOXK2	forkhead box K2	1.38
NM 002086	GRB2	growth factor receptor-bound protein 2	1.38
NM 002868	RAB5B	RAB5B, member RAS oncogene family	1.37
NM 002768	PCOLN3	procollagen (type III) N-endopeptidase	1.37
NM 014742	TM9SF4	transmembrane 9 superfamily protein member 4	1.37
NM 004344	CETN2	centrin, EF-hand protein, 2	1.37
NM 002881	RALB	v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)	1.36
NM 004099	STOM	stoma tin	1.36
NM 031844	HNRPU	heterogeneous nuclear ribonucleoprotein U (scaffold attachment factor A)	1.36
NM 000480	AMPD3	adenosine monophosphate deaminase (isoform E)	1.35
NM 006561	CUGBP2	CUG triplet repeat RNA binding protein 2	1.35
NM 152879	DGKD	diaeylglycerol kinase delta 130kDa	1.35
NM 138558	PPP1R8	protein phosphatase 1 reQulatory (inhibitor) subunit 8	1.35
NM 004941	DHX8	DEAH (Asp-Glu-Ala-His) box polypeptide 8	1.34
NM 021079	NMT1	N-myristoyltransferase 1	1.33
NM 004622	TSN	translin	1.33
NM 002473	MYH9	myosin, heavy polypeptide 9, non-muscle	1.33
NM 006889	CD86	CD86 antigen (CD28 antigen ligand 2, B7-2 antigen)	1.33
NM 004383	CSK	c-src tyrosine kinase	1.33
NM 004317	ASNA1	arsA arsenite transoorter ATP-binding homolog 1 (bacterial)	1.33
NM 024298	LENG4	leukocyte receptor cluster (LRC) member 4	1.32
NM 001912	CTSL	cathepsin L	1.32
NM 001357	DHX9	DEAH (Asp-Glu-Ala-His) box polypeptide 9	1.32
NM 006849	PDIP	protein disulfide isomerase, pancreatic	1.32
NM_018457	DKFZP56 4J157	DKFZ, 0564J157 protein	1.31
NM 024880	TCF7L2	transcription factor 7-like 2 (T-cell specific, HMG-box)	1.31
NM 002081	GPC1	glypican 1	1.31
NM 004235	KLF4	Kruppel-like factor 4 (gut)	1.31

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NM 005565	LCP2	lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa)	1.30
NM 002667	PLN	phospholamban	1.30
NM 004946	DOCK2	dedicator of cytokinesis 2	1.30
NM 002035	FVT1	follicular lymphoma variant translocation 1	1.29
NM 002865	RAB2	RAB2 member RAS oncogene family	1.29
NM 002806	PSMC6	proteasome (prosome macropain) 26S subunit ATPase 6	1.29
NM 004240	TRIP 10	thyroid hormone receptor interactor 10	1.28
NM 003760	EIF4G3	eukaryotic translation initiation factor 4 gamma, 3	1.28
NM 005151	USP14	ubiquitin specific protease 14 (tRNA quanine transglycosylase)	1.28
NM 015922	H105E3	NAD(P) deoendent steroid dehydropenase-like	1.27
NM 033306	CASP4	caspase 4 apoptosis-related cysteine protease	1.27
NM 198189	COPS8	COP9 constitutive photomorphogenic homolog subunit 8 (Arabidopsis)	1.27
NM 001933	DLST	dihydrolipoamide S-succinyltransferase (E2 component of 2-oxo-qlutarate complex)	1.27
NM 015004	K1AA0116	K1AA0116 protein	1.27
NM 033362	MRPS12	mitochondrial ribosomal protein S12	1.27
NM 004180	TANK	TRAF family member-associated NFKB activator	1.26
NM 014734	K1AA0247	K1AA0247	1.26
NM 005271	GLUD1	glutamate dehydropenase 1	1.25
NM 003009	SEPW1	selenoprotein W, 1	1.25
NM 182641	FALZ	fetal Alzheimer antigen	1.24
NM 007362	NCBP2	nuclear cap binding protein subunit 2 20kDa	1.24
NM 004292	RIN1	Ras and Rab interactor 1	1.24
NM 014608	CYFIP1	cytoplasmic FMR1 interacting protein 1	1.23
NM 022333	TIAL1	TIA1 cytotoxic oranule-associated RNA binding protein-like 1	1.23
NM 003126	SPTA1	spectrin alpha erythrocytic 1 (elliptocytosis 2)	1.22
NM 014602	PIK3R4	phosphoinositide-3-kinase regulatory subunit 4, pl50	1.18
NM 002194	INPP1	inositol polyphosphate-l-phosphatase	1.16

Note: Accession IDs “NM_XXXX” are uniquely assigned to each gene by National Center for Biotechnology Information (NCBf) (http://www.ncbi. nlm.nih.gov/sites/entrez?db=nuccore).

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Table 7: Commonly Downregulated Genes in Pancreatic Cancer
Accession	Gene Symbol	Gene Name	FC
NM 006499	LGALS8	galoctosite-binding, soluble, 8 (galectin 8)	0.87
NM 000466	PEX1	peroxisome biogenesis factor 1	0.81
NM 002766	PRPSAP1	phosphoribosyl pyrophosphate synthetase-associated protein 1	0.81
NM 147131	GALT	galactose-l-phosphate uridylyltransferase	0.80
NM 002101	GYPC	glycophorin C (Gerbich blood group)	0.80
NM 002880	RAF1	v-raf-1 murine leukemia viral oncogene homolog 1	0.80
NM 004649	C218rf33	chromosome 21 open reading frame 33	0.80
NM 003262	TLOC1	translocation protein 1	0.79
NM 147223	NCOA1	nuclear receptor coactivator 1	0.79
NM 007062	PWP1	nuclear phosphoprotein similar to S. cerevisiae PWP1	0.79
NM 005561	LAMP1	lysosomal-associated membrane protein 1	0.79
NM 006810	PDIR	for protein disulfide isomerase-related	0.78
NM 033360	KRAS2	v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog	0.77
NM 001513	GSTZ1	glutathione transferase zeta 1 (maleylacetoacetate isomerase)	0.77
NM 006184	NUCB1	nucleobindin 1	0.77
NM 001634	AMD1	adenosylmethionine decarboxylase 1	0.76
NM 006749	SLC20A2	solute carrier family 20 (phosphate transporter), member 2	0.76
NM 003144	SSR1	signal sequence receptor alpha (translocon-associated protein alpha)	0.76
NM 004606	TAF1	TAF1 RNA polymerase II, TATA box binding protein (TBP)-associated factor 250kDa	0.75
BX648788		MRNA; cDNA DKFZP686M12165 (from clone DKFZP686M12165)	0.75
NM 004035	ACOX1	acyl-Coenzyme A oxidase 1 palmitoyl	0.74
NM 000287	PEX6	peroxisomal biogenesis factor 6	0.73
NM 003884	PCAF	p300/CBP-associated factor	0.73
NM 006870	DSTN	destrin (actin depolymerizing factor)	0.73
NM 001604	PAX6	paired box gene 6 (aniridia keratitis)	0.72
NM 000722	CACNA2 DI	calcium channel voltage-dependent alpha 2/delta subunit 1	0.72
NM 033022	RPS24	ribosomal protein S24	0.72
NM 004563	PCK2	phosphoenolpyruvate carboxykinase 2 (mitochondrial)	0.72
NM 002602	PDE6G	phosphodiesterase 6G cGMP-specifie, rod, gamma	0.72
NM 001889	CRYZ	crystalline, zeta (quinone reductase)	0.72
NM 002339	LSP1	lymphocyte-specific protein 1	0.72
NM 016848	SHC3	src homology 2 domain containing transforming protein C3	0.71
NM 002906	RDX	radixin	0.71
NM 007014	WWP2	Nedd-4-like ubiquitin-protein ligase	0.71
NM 000414	HSD17B4	hydroxysteroid (17-beta) dehydrogenase 4	0.71
NM 001127	AP1B1	adaptor-related protein complex 1, beta 1 subunit	0.71
NM 002402	MEST	mesoderm specific transcript homolog (mouse)	0.70
NM 033251	RPL13	ribosomal protein L13	0.70
NM 139069	MAPK9	mitogen-activated protein kinase 9	0.70
NM 002913	RFC1	replication factor C (activator 1) 1, 145kDa	0.70
NM 000487	ARSA	arvlsulfatase A	0.70
NM 006973	ZNF32	zinc finger protein 32 (KOX 30)	0.70
NM 005310	GRB7	growth factor receptor-bound protein 7	0.70
NM 005962	MX11	MAX interacting protein 1	0.69
NM 005359	MADH4	MAD, mothers against decapentaplegic homolog 4 (Drosophila)	0.69
NM 002340	LSS	lanosterol synthase (2 3-oxidosqualene-lanosterol cyclase)	0.69
NM 003684	MKNK1	MAP kinase-interacting serine/threonine kinase 1	0.68
NM 005671	D8S2298 E	reproduction 8	0.68
NM 000309	PPOX	protoporphyrinogen oxidase	0.68
NM 000994	RPL32	ribosomal protein L32	0.68
NM 000972	RPL7A	ribosomal protein L7a	0.68
NM 005101	G1P2	interferon, alpha-inducible protein (clone IFI-15K)	0.67
NM 001129	AEBP1	AE binding protein 1	0.67
NM 001011	RPS7	ribosomal protein S7	0.67
NM 001153	ANXA4	annexin A4	0.67
NM 012335	MY01F	myosin IF	0.66
NM_005007	NFKBIL1	nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 1	0.66
NM 001870	CP A3	carboxypeptidase A3 (mast cell)	0.66
NM 181826	NF2	neurofibromin 2 (bilateral acoustic neuroma)	0.66
NM 000285	PEPD	peptidase D	0.66
NM 006180	NTRK2	neurotrophic tyrosine kinase, receptor type 2	0.66
NM 000543	SMPD1	sphingomyelin phosphodiesterase 1, acid lysosomal (acid sphinagmyelinase)	0.66
NM 001459	FLT3LG	fms-related tyrosine kinase 3 ligand	0.65
NM 003750	EIF3S10	eukaryotic translation initiation factor 3, subunit 10 theta, 150/170kDa	0.65

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NM 005570	LMAN1	lectin mannose-binding, 1	0.65
NM 004409	DMPK	dystrophia myotonica-protein kinase	0.65
NM 172159	KCNAB1	potassium voltage-gated channel, shaker-related subfamily, beta member 1	0.65
XM 352750	COL14A1	collagen, type XIV, alpha 1 (undulin)	0.65
NM 001731	BTG1	B-cell translocation gene 1, anti-proliferative	0.65
NM 000884	IMPDH2	IMP (inosine monophosphate) dehydrogenase 2	0.64
NM 001885	CRYAB	crystallin, alpha B	0.64
NM 000240	MAOA	monoamine oxidase A	0.64
NM 003136	SRP54	siqnal recognition particle 54kDa	0.63
NM_000281	PCBD	6-pyruvoyl-tetrahydropterin synthase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1)	0.63
NM 005729	PPIF	peptidylprolpyl isomerase F (cyclophilin F)	0.63
NM 006481	TCF2	transcription factor 2, hepatic; LF-B3' variant hepatic nuclear factor	0.63
NM 002089	CXCL2	chemokine (C-X-C motif) liqand 2	0.63
NM 001961	EEF2	eukaryotic translation elonqation factor 2	0.63
NM 001801	CDO1	cysteine dioxygenase type I	0.63
NM 006389	HYOU1	hypoxia up-regulated 1	0.63
XM 167711	ITGA8	integrin, alpha 8	0.62
NM 014765	TOMM20	translocase of outer mitochondrial membrane 20 homolog (yeast)	0.62
NM 006714	SMPDL3 A	sphingomyelin phosphodiesterase, acid-like 3A	0.62
NM 000016	ACAOM	acyl-Coenzyme A dehydrogenase C-4 to C-12 straiqht chain	0.62
NM 003924	PHOX2B	paired-like homeobox 2b	0.62
NM 002078	GOLGA4	golgi autoantigen, golgin subfamily a 4	0.62
NM 002736	PRKAR2 B	protein kinase cAMP-dependent, requlatory, type II beta	0.62
BQ217469	K1AA0114	K1AA0114 gene product	0.61
NM 006307	SRPX	sushi-repeat-containing protein X-linked	0.61
NM 002184	IL6ST	interleukin 6 siqnal transducer (gpl30 oncostatin M receptor)	0.61
NM 153186	ANKR015	ankyrin repeat domain 15	0.61
NM 003038	S1C1A4	solute carrier family 1 (glutamate/neutral amino acid transporter), member 4	0.60
NM 006195	PBX3	pre-B-cell leukemia transcription factor 3	0.60
NM 000327	ROM1	retinal outer segment membrane protein 1	0.60
NM 003463	PTP4A1	protein tyrosine phosphatase type IVA, member 1	0.60
NM 001520	GTF3C1	general transcription factor iiiC polypeptide 1 alpha 220kDa	0.60
NM 006277	ITSN2	intersectin 2	0.59
NM 000985	RPL17	ribosomal protein L17	0.59
NM 000909	NPY1R	neuropeptide Y receptor Y1	0.59
NM 001014	RPS10	ribosomal protein S10	0.59
NM 022307	ICA1	islet cell autoantigen 1 69kDa	0.58
NM 002567	PBP	prostatic binding protein	0.58
NM 012324	MAPK81P 2	mitogen-activated protein kinase 8 interacting protein 2	0.58
NM 004490	GRB14	growth factor receptor-bound protein 14	0.58
NM 004733	SLC33A1	solute carrier family 33 (acetyl-CoA transporter), member 1	0.57
NM 002197	AC01	aconitase 1, soluble	0.57
NM 000505	F12	coagulation factor Xii (Hageman factor)	0.57
NM 005010	NRCAM	neuronal cell adhesion molecule	0.56
NM 006963	ZNF22	zinc finger protein 22 (KOX 15)	0.56
NM 006827	TMP21	transmembrane trafficking protein	0.55
NM 004394	DAP	death-associated protein	0.54
NM 001089	ABCA3	ATP-binding cassette, sub-family A (ABC), member 3	0.54
NM 004470	FKBP2	FK506 binding protein 2, 13kDa	0.53
NM 005749	TOB1	transducer of ERBB2, 1	0.53
NM 001355	DDT	D-dopachrome tautomerase	0.53
NM 002111	HD	huntington (Huntington disease)	0.53
NM 002635	S1C25A3	solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3	0.53
NM 005596	NFIB	nuclear factor I/B	0.53
NM 006273	CCL7	chemokine (C-C motif) liqand 7	0.53
NM 001013	RPS9	ribosomal protein S9	0.52
NM 001551	IGBP1	immunoglobulin (CD79A) binding protein 1	0.52
NM 004498	ONECUT1	one cut domain, family member 1	0.52
NM 004484	GPC3	glypican 3	0.52
NM 130797	DPP6	dipeptidylpeptidase 6	0.52
NM 000746	CHRNA7	cholineragic receptor, nicotinic, alpha polypeptide 7	0.51
NM 001756	SERPINA 6	serine (or cysteine) proteinase inhibitor, clade A (alpha-1 antiproteinase antitrypsin), member 6	0.51
NM 001327	CTAG1	cancer/testis antigen 1	0.51
NM 003651	CSDA	cold shock domain protein A	0.50
NM 005848	IRLB	c-myc promoter-binding protein	0.50
BC040073	H19	H19, imprinted maternally expressed untranslated mRNA	0.50
NM 002228	JUN	v-jun sarcoma virus 17 oncogene homolog (avian)	0.49
NM 000795	DRD2	dopamine receptor D2	0.48
NM 002084	GPX3	glutathione peroxidase 3 (plasma)	0.48

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NM 002716	PPP2R1B	protein phosphatase 2 (formerly 2A), regulatory subunit A (PR 65), beta isoform	0.48
NM 005166	APLP1	amyloid beta (A4) precursor-like protein 1	0.48
NM 005911	MAT2A	methionine adenosyltransferase II, alpha	0.47
NM 000208	INSR	insulin receptor	0.47
NM 170736	KCNJ15	potassium inwardly-rectifying channel, subfamily J, member 15	0.47
NM 001190	BCAT2	branched chain aminotransferase 2, mitochondrial	0.47
NM 005336	HDLBP	hiqh density lipoprotein binding protein (viqilin)	0.46
NM 001076	UGT2B15	UDP glycosyltransferase 2 family, polypeptide B15	0.46
NM 001152	SLC25A5	solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator, member 5	0.46
NM 002729	HHEX	hematopoietically expressed homeobox	0.46
NM 002847	PTPRN2	protein tyrosine phosphatase, receptor type, N polypeptide 2	0.44
NM 000447	PSEN2	presenilin 2 (Alzheimer disease 4)	0.44
NM 152868	KCNJ4	potassium inwardly-rectifying channel, subfamily J, member 4	0.44
NM 001759	CCND2	cyclin D2	0.44
NM 000316	PTHR1	parathyroid hormone receptor 1	0.44
NM 001612	ACRV1	acrosomal vesicle protein 1	0.43
NM 002467	MYC	v-mc myelocytomatosis viral oncogene homolog (avian)	0.43
NM 004454	ETV5	ets variant gene 5 (ets-related molecule)	0.43
NM 002846	PTPRN	protein tyrosine phosphatase, receptor type N	0.43
NM 005622	SAH	SA hypertension-associated homolog (rat)	0.42
NM 001989	EVX1	eve, even-skipped homeo box homolog 1 (Drosophila)	0.42
NM 000166	GJB1	gap junction protein, beta 1, 32kDa (connexin 32, Charcot-Marie-Tooth neuropathy, X-linked)	0.42
NM 014685	HERPUD 1	homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1	0.42
NM 001735	C5	complement component 5	0.41
NM 005504	BCAT1	branched chain aminotransferase 1, ctyosolic	0.41
NM 006808	SEC61B	Sec61 beta subunit	0.40
NM 006751	SSFA02	sperm specific antigen 2	0.39
NM 005947	MT1B	metallothionein IB (functional)	0.38
NM 005576	LOXL1	lysyl oxidase-like 1	0.37
NM 005627	SGK	serum/glucocorticoid regulated kinase	0.36
NM 004683	RON	regucalcin (senescence marker protein-30)	0.36
NM 00918	P4HB	procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide (protein disulfide isomerase; thyroid hormone binding protein p55)	0.36
BC044862		Macrophage stimulating 1 (hepatocyte growth factor-like), mRNA (cDNA clone IMAGE:4821945), with apparent retained intron	0.35
NM 005952	MT1X	metallothionein IX	0.35
NM 000429	ΜΑΤΙΑ	methionine adenosyltransferase 1, alpha	0.35
NM 004010	DMD	dystrophin (muscular dystrophy, Duchenne and Becker types)	0.34
NM 000689	ALDH1A1	aldehyde dehydrogenase 1 family, member Al	0.34
NM 002889	RARRES2	retinoic acid receptor responder (tazarotene induced) 2	0.33
NM 006280	SSRA	signal sequence receptor, delta (translocon-associated protein delta)	0.33
NM 003819	PABPC4	poly(A) binding protein, cytoplasmic 4 (inducible form)	0.32
NM 000755	CRAT	carnitine aceltyltransferase	0.32
NM 015684	ATP5S	ATP synthase, H+ transporting, mitochondrial F0 complex, subunit s (factor B)	.030
NM 033200	BC002942	hypothetical protein BC002942	0.30
BCG986717		Transcribed sequences	0.29
NM 148923	CYB5	cytochrome b-5	0.29
NM 000609	CXCL12	chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1)	0.29
NM 001979	EPHX2	epoxide hydrolase 2, cytoplasmic	0.28
NM 001332	CTNND2	catenin (caherin-associated protein), delta 2 (neural plakophilin-related arm-repeat protein)	0.27
NM 001831	CLU	clusterin (complement lysis inhibitor, SP-40,40, sulfated glycoprotein 2, testosterone-repressed prostate message 2, apolipoprotein J)	0.27
NM 005080	XBP1	X-box binding protein 1	0.27
NM 000156	GAMT	guanidinoacetate N-methyltransferase	0.27
NM 182848	CLDN10	claudin 10	0.26
NM 000065	C6	complement component 6	0.26
NM 000128	Fll	coagulation factor XI (plasma thromboplasin antecedent)	0.24
NM 003822	MR5A2	nuclear receptor subfamily 5, group A, member 2	0.24
NM 006406	PRDX4	peroxiredoxin 4	0.21
BM799844	BNIP3	BCL2/adenovirus E1B 19kDa interacting protein 3	0.21
NM 018646	TRPV6	transient receptor potential cation channel, subfamily V, member 6	0.21
NM 005013	NUCB2	nucleobindin 2	0.21
NM 000624	SERPINA 3	serine (or cysteine) proteinase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3	0.19
NM 005065	SEL IL	sel-1 suppressor of lin-12-like (C. elegans)	0.18
NM 198235	RNASE 1	ribonuclease, RNase A family, 1 (pancreatic)	0.17
NM 006498	LGALS2	lectin, galactoside-binding, soluble, 2 (galectin 2)	0.16
NM 002899	RBP1	retinol binding protein 1, cellular	0.12
NM 004413	DPEP1	dipeptidase 1 (renal)	0.12
NM 021603	FXYD2	FXYD domain contaning ion transport regulator 2	0.09
NM 138938	PAP	pancreatitis-associated protein	0.08

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NM 201553	FGL	fibrinogen-like 1	0.07
NM 001482	GATM	glycerine amidinotransferase (L-arrginine: glycine amidinotransferase)	0.04
NM 033240	ELA2A	elastase 2a	0.02
NM 000101	CYBA	cytochrome b-245, alpha polypeptide	0.02

Note: Accession IDs “NM_XXXX” are uniquely assigned to each gene by National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/sites/entrez?db=nuccore).

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2017272272 07 Dec 2017 ible 8. microRNAs that are up-regulated in glioblastoma cells.

Fold change	microRNA
Up 10X	miR-10b, miR-10a, miR-96
Up 2-1 OX	miR-182, miR-199b, miR-21, miR124, miR-199a, miR-199-s, miR-199a, miR-106b, miR-15b, miR-188, miR148a, miR-104, miR-224, miR-368, miR-23a, miR-21 ON, miR-183, miR- 25, miR-200cN, miR-373, miR-17-5p, let-7a, miR-16, miR-19b, miR-26a, miR-27a, miR-92, miR-93, miR-320 and miR-20
Up 1-2 X	miR-143, miR-186. miR-337, miR30a-3p, miR-355, miR-324-3p etc.

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Fold change	microRNA
Down 10X	miR-218, miR-124a, miR-124b, miR137, miR-184, miR-129, miR-33, miR139, miR-128b, miR-128a, miR-330, miR-133a, miR-203, miR-153, miR326, miR-105, miR-338, miR-133b, miR-132, miR-154, miR-29bN
Down 2-1 OX	miR-7N, miR-323, miR-219, miR-328, miR-149, miR-122a, miR-321, miR107, miR-190, miR-29cN, miR-95, miR-154, miR-221, miR-299, miR-31, miR-370, miR-331, miR-342, miR-340

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Table 10. MMP genes contained within microvesicles isolated from glioblastoma cell line.

Gene Symbol	Accession ID	Gene Description
MMP1	AK097805	Homo sapiens cDNA FLJ40486 fis, clone TESTI2043866. [AK097805] Homo sapiens matrix metallopeptidase 8 (neutrophil collagenase)
MMP8	NM_002424	(MMP8), mRNA [NM_002424] Homo sapiens matrix metallopeptidase 12 (macrophage elastase)
MMP12	NM_002426	(MMP12), mRNA [NM_002426] Homo sapiens matrix metallopeptidase 15 (membrane-inserted)
MMP15	NM_002428	(MMP15), mRNA [NM_002428] Homo sapiens matrix metallopeptidase 20 (enamelysin) (MMP20),
MMP20	NM_004771	mRNA [NM_004771] Homo sapiens matrix metallopeptidase 21 (MMP21), mRNA
MMP21	NM_147191	[NM_147191] Homo sapiens matrix metallopeptidase 24 (membrane-inserted)
MMP24	NM_006690	(MMP24), mRNA [NM_006690] Homo sapiens matrix metallopeptidase 26 (MMP26), mRNA
MMP26	NM_021801	[NM_021801] Homo sapiens matrix metallopeptidase 27 (MMP27), mRNA
MMP27	NM_022122	[NM_022122]

Note: Gene symbols are standard symbols assigned by Entrz Gene (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene). Accession IDs are uniquely assigned to each gene by National Center for Biotechnology Information (NCBI) (http://www.ncbi. nlm.nih.gov/sites/entrez?db=nuccore).

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2017272272 07 Dec 2017 'able 11. Genes containing omatic mutations in lioblastoma adapted from be result of TCGA project McLendon et al., 2008).

Hugo Gene Symbol	EntrezGeneJd
A2M	2
A2M	2
A2M	2
ABCA3	21
ABCC4	10257
ABCC4	10257
ABCC4	10257
ADAM12	8038
ADAM15	8751
ADAMTSL3	57188
ADAMTSL3	57188
ADM	133
AIFM1	9131
AKAP2	11217
AKAP2	11217
ALK	238
ANK2	287
ANK2	287
ANK2	287
ANK2	287
ANK2	287
ANXA1	301
ANXA7	310
AOC3	8639
AOC3	8639
APBB1IP	54518
APC	324
ARNT	405
AS PM	259266
AS PM	259266
ASXL1	171023
ASXL1	171023
ATM	472
ATM	472
ATM	472
ATP6V1 E1	529
ATR	545
AVIL	10677
AXL	558
BAI3	577
BAI3	577
BAI3	577
BAMBI	25805
BCAR1	9564
BCAR1	9564
BCL11A	53335

Hugo Gene Symbol BCL11A	Entrez_Gene_ld 53335	Hugo Gene Symbol CHEK2	Entrez_Gene_ld 11200
BCL11A	53335	CHEK2	11200
BCL11A	53335	CHEK2	11200
BCL11A	53335	CHEK2	11200
BCL11A	53335	CHEK2	11200
BCL2L13	23786	CHEK2	11200
BCR	613	CHEK2	11200
BMPR1A	657	CHEK2	11200
BRCA1	672	CHEK2	11200
BRCA2	675	CHEK2	11200
BRCA2	675	CHEK2	11200
BRCA2	675	CHI3L2	1117
BTK	695	CHIC2	26511
C18orf25	147339	CHL1	10752
C20orf160	140706	CHL1	10752
C20orf160	140706	CMTM3	123920
C22orf24	25775	CNTFR	1271
C6orf60	79632	COL11A1	1301
C6orf60	79632	COL1A1	1277
C9orf72	203228	COL1A1	1277
CAND1	55832	COL1A1	1277
CASP9	842	COL1A1	1277
CAST	831	COL1A2	1278
CAST	831	COL1A2	1278
CAST	831	COL3A1	1281
CBL	867	COL3A1	1281
CBL	867	COL3A1	1281
CCR5	1234	COL3A1	1281
CD46	4179	COL5A1	1289
CDC123	8872	COL6A2	1292
CDKL5	6792	COL6A2	1292
CDKN2A	1029	COL6A2	1292
CDKN2A	1029	CRLF1	9244
CDKN2A	1029	CSF3R	1441
CENPF	1063	CSF3R	1441
CENPF	1063	CSMD3	114788
CENTG1	116986	CSMD3	114788
CENTG1	116986	CSNK1E	1454
CES3	23491	CTNNB1	1499
CES3	23491	CTSH	1512
CHAT	1103	CTSH	1512
CHAT	1103	CYLD	1540
CHD5	26038	CYP27B1	1594
CHEK1	1111	CYP27B1	1594
CHEK1	1111	CYP3A4	1576
CHEK1	1111	DCX	1641
CHEK1	1111	DDIT3	1649
CHEK2	11200	DDR2	4921
CHEK2	11200	DDR2	4921
CHEK2	11200	DDR2	4921
CHEK2	11200	DES	1674
CHEK2	11200	DES	1674

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Hugo Gene Symbol	Entrez_Gene_ld	Hugo Gene Symbol	Entrez_Gene_ld	Hugo Gene Symbol	Entrez_Gene_ld
DGKD	8527	EPHA4	2043	FN1	2335
DGKG	1608	EPHA4	2043	FOXO3	2309
DHTKD1	55526	EPHA6	285220	FOXO3	2309
DMBT1	1755	EPHA7	2045	FOXO3	2309
DMRT3	58524	EPHA7	2045	FRAP1	2475
DOCK1	1793	EPHA8	2046	FURIN	5045
DOCK1	1793	EPHA8	2046	FURIN	5045
DOCK1	1793	EPHB1	2047	FURIN	5045
DOCK8	81704	ERBB2	2064	GARNL3	84253
DOCK8	81704	ERBB2	2064	GATA3	2625
DPYSL4	10570	ERBB2	2064	GATA3	2625
DPYSL4	10570	ERBB2	2064	GCLC	2729
DST	667	ERBB2	2064	GDF10	2662
DST	667	ERBB2	2064	GLI1	2735
DST	667	ERBB2	2064	GLI3	2737
DST	667	ERBB2	2064	GLTSCR2	29997
DST	667	ERBB2	2064	GNAI1	2770
DST	667	ERBB2	2064	GNAS	2778
DST	667	ERBB2	2064	GNAS	2778
DST	667	ERBB3	2065	GPR78	27201
DTX3	196403	ESR1	2099	GRIA2	2891
EGFR	1956	ETNK2	55224	GRLF1	2909
EGFR	1956	EYA1	2138	GRN	2896
EGFR	1956	EYA1	2138	GRN	2896
EGFR	1956	F13A1	2162	GSTM5	2949
EGFR	1956	FBXW7	55294	GSTM5	2949
EGFR	1956	FBXW7	55294	GSTM5	2949
EGFR	1956	FGFR1	2260	GSTM5	2949
EGFR	1956	FGFR1	2260	GSTM5	2949
EGFR	1956	FGFR2	2263	GSTM5	2949
EGFR	1956	FGFR3	2261	GSTM5	2949
EGFR	1956	FKBP9	11328	GSTM5	2949
EGFR	1956	FKBP9	11328	GSTM5	2949
EGFR	1956	FKBP9	11328	GYPC	2995
EGFR	1956	FKBP9	11328	HCK	3055
EGFR	1956	FKBP9	11328	HCK	3055
EGFR	1956	FKBP9	11328	HELB	92797
EGFR	1956	FKBP9	11328	HLA-E	3133
EGFR	1956	FKBP9	11328	HLA-E	3133
EGFR	1956	FKBP9	11328	HLA-E	3133
EGFR	1956	FKBP9	11328	HLA-E	3133
EGFR	1956	FKBP9	11328	HS3ST3A1	9955
EGFR	1956	FKBP9	11328	HSP90AA1	3320
EGFR	1956	FKBP9	11328	HSP90AA1	3320
ELAVL2	1993	FLI1	2313	HSPA8	3312
EP300	2033	FLI1	2313	HSPA8	3312
EP300	2033	FLT1	2321	HSPA8	3312
EP400	57634	FLT4	2324	HSPA8	3312
EP400	57634	FN1	2335	HSPA8	3312
EP400	56734	FN1	2335	HSPA8	3312
EPHA2	1969	FN1	2335	HSPA8	3312
EPHA3	2042	FN1	2335	ID3	3399
EPHA3	2042	FN1	2335	IFITM3	10410

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Hugo Gene Symbol IFITM3	Entrez_Gene_ld 10410	Hugo Gene Symbol LRRN2	Entrez_Gene_ld 10446	Hugo Gene Symbol NF1	Entrez_Gene_ld 4763
IFITM3	10410	LTF	4057	NF1	4763
IFITM3	10410	LTF	4057	NF1	4763
IFITM3	10410	LYN	4067	NF1	4763
IFITM3	10410	MAG	4099	NF1	4763
IFITM3	10410	MAP3K6	9064	NF1	4763
IL1RL1	9173	MAPK13	5603	NF1	4763
IL31	386653	MAPK7	5598	NF1	4763
ILK	3611	MAPK8IP2	23542	NF1	4763
ING4	51147	MAPK8IP3	23162	NF1	4763
ING4	51147	MAPK9	5601	NF1	4763
ING4	51147	MAPK9	5601	NF1	4763
INHBE	83729	MARK1	4139	NF1	4763
IQGAP1	8826	MARK1	4139	NF1	4763
IRAK3	11213	MDM2	4193	NMBR	4829
IRS1	3667	MDM4	4194	NMBR	4829
IRS1	3667	MEOX2	4223	NOS3	4846
ISL1	3670	MET	4233	NOS3	4846
ITGAL	3683	MET	4233	NOTCH1	4851
ITGB2	3689	MET	4233	NOTCH1	4851
ITGB2	3689	MLH1	4292	NRXN3	9369
ITGB2	3689	MLH1	4292	NTRK3	4916
ITGB3	3690	MLH1	4292	NUMA1	4926
ITGB3	3690	MLL4	9757	NUP214	8021
ITGB3	3690	MLL4	9757	ONECUT2	9480
ITGB3	3690	MLL4	9757	OR5P2	120065
ITGB3	3690	MLLT7	4303	PAX5	5079
JAG1	182	MMD2	221938	PDGFRA	5156
KIAA1632	57724	MN1	4330	PDGFRA	5156
KIF3B	9371	MSH2	4436	PDGFRA	5156
KIT	3815	MSH2	4436	PDGFRB	5159
KIT	3815	MSH6	2956	PDGFRB	5159
KIT	3815	MSH6	2956	PDK2	5164
KLF4	9314	MSH6	2956	PDPK1	5170
KLF4	9314	MSH6	2956	PDZD2	23037
KLF6	1316	MSI1	4440	PDZD2	23037
KLF6	1316	MSI1	4440	PHLPP	23239
KLK8	11202	MTAP	4507	PI15	51050
KPNA2	3838	MUSK	4593	PI15	51050
KPNA2	3838	MYCN	4613	PIK3C2A	5286
KRAS	3845	MYCN	4613	PIK3C2B	5287
KSR2	283455	MYLK2	85366	PIK3C2G	5288
KSR2	283455	MYO3A	53904	PIK3C2G	5288
KTN1	3895	MYST4	23522	PIK3C2G	5288
LAMP1	3916	MYST4	23522	PIK3C2G	5288
LAMP1	3916	MYST4	23522	PIK3C2G	5288
LAX1	54900	MYST4	23522	PIK3CA	5290
LCK	3932	NBN	4683	PIK3CA	5290
LDHA	3939	NDUFA10	4705	PIK3CA	5290
LDHA	3939	NEK10	152110	PIK3CA	5290
LGALS3BP	3959	NELL2	4753	PIK3CA	5290
LGALS3BP	3959	NF1	4763	PIK3R1	5295
LGALS3BP	3959	NF1	4763	PIK3R1	5295

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Hugo Gene Symbol PIK3R1	Entrez_Gene_ld 5295	Hugo Gene Symbol PTEN	Entrez_Gene_ld 5728	Hugo Gene Symbol SLIT2	Entrez_Gene_ld 9353
PIK3R1	5295	PTEN	5728	SMAD2	4087
PIK3R1	5295	PTEN	5728	SMAD4	4089
PIK3R1	5295	PTEN	5728	SNF1LK2	23235
PIM1	5292	PTEN	5728	SNF1LK2	23235
PLAG1	5324	PTEN	5728	SNX13	23161
PML	5371	PTEN	5728	SOCS1	8651
PMS2	5395	PTEN	5728	SOX11	6664
P0U2F1	5451	PTEN	5728	SOX11	6664
PPP2R5D	5528	PTEN	5728	SPARC	6678
PRKCA	5578	PTEN	5728	SPDEF	25803
PRKCA	5578	PTEN	5728	SPN	6693
PRKCB1	5579	PTEN	5728	SPRED3	399473
PRKCB1	5579	PTK2B	2185	SRPK2	6733
PRKCD	5580	PTPN11	5781	ST7	7982
PRKCD	5580	PTPN11	5781	STAT1	6772
PRKCD	5580	RADIL	55698	STAT3	6774
PRKCD	5580	RADIL	55698	STK32B	55351
PRKCD	5580	RB1	5925	STK36	27148
PRKCD	5580	RB1	5925	SYP	6855
PRKCZ	5590	RB1	5925	TAF1	6872
PRKCZ	5590	RB1	5925	TAF1	6872
PRKD2	25865	RB1	5925	TAOK3	51347
PRKD2	25865	RB1	5925	TAS1R1	80835
PRKDC	5591	RB1	5925	TBK1	29110
PRKDC	5591	RB1	5925	TBK1	29110
PRKDC	5591	RB1	5925	TCF12	6938
PROX1	5629	RINT1	60561	TCF12	6938
PSMD13	5719	RIPK4	54101	TCF12	6938
PSMD13	5719	RNF38	152006	TERT	7015
PSMD13	5719	ROR2	4920	TERT	7015
PTCH1	5727	ROR2	4920	TGFBR2	7048
PTCH1	5727	ROS1	6098	TIMP2	7077
PTEN	5728	ROS1	6098	TNC	3371
PTEN	5728	RPN1	6184	TNC	3371
PTEN	5728	RPS6KA3	6197	TNC	3371
PTEN	5728	RTN1	6252	TNFRSF11B	4982
PTEN	5728	RUNX1T1	862	TNK2	10188
PTEN	5728	RYR3	6263	TNK2	10188
PTEN	5728	RYR3	6263	TNK2	10188
PTEN	5728	SAC	55811	TNK2	10188
PTEN	5728	SAC	55811	TOP1	7150
PTEN	5728	SEMA3B	7869	TP53	7157
PTEN	5728	SERPINA3	12	TP53	7157
PTEN	5728	SERPINE1	5054	TP53	7157
PTEN	5728	SHH	6469	TP53	7157
PTEN	5728	SLC12A6	9990	TP53	7157
PTEN	5728	SLC12A6	9990	TP53	7157
PTEN	5728	SLC25A13	10165	TP53	7157
PTEN	5728	SLC25A13	10165	TP53	7157
PTEN	5728	SLC2A2	6514	TP53	7157
PTEN	5728	SLIT2	9353	TP53	7157
PTEN	5728	SLIT2	9353	TP53	7157

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Hugo Gene Symbol	Entrez_Gene_ld
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TP53	7157
TPBG	7162
TRIM24	8805
TRIM3	10612
TRIM33	51592
TRIP6	7205
TRRAP	8295
TRRAP	8295
TSC1	7248

Hugo Gene Symbol	Entrez_Gene_ld
TSC2	7249
TSC2	7249
TSC2	7249
LJNG	7374
UPF2	26019
UPF2	26019
VAV2	7410
VLDLR	7436
WNT2	7472
ZEB1	6935
ZEB1	6935
ZNF384	171017
ZNF384	171017

Note: Hugo Gene Symbols are assigned to individual genes by HUGO Gene Nomenclature Committee (http ://ww w. genenames. org/). Entrez_Gene_Ids are assigned to individual genes by Entrz Gene (http://www.ncbi.nlm.nih.gov/sites/ent rez?db=gene).

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’able 12. Genes containing omatic mutations in	Gene symbol	Accession ID	Gene symbol	Accession ID
lioblastoma adapted from	ADAM29	CCDS3823.1	APOB	CCDS 1703.1
tie paper by Parsons et. al.	ADAMTS1	NM 006988	APOBEC3G	CCDS 13984.1
Parsons et al., 2008)	AD AMTS 13	CCDS6970.1	APRG1	NM_178339
		AD AMTS 17	CCDS10383.1	AQP10	CCDS 1065.1
		ADAMTS20	NM 175851	AR	CCDS14387.1
Gene symbol	Accession ID
		ADAMTS4	CCDS 1223.1	ARD1B	ENST00000286794
		ADAMTS8	NM 007037	ARHGAP4	CCDS 14736.1
A2M	NM 000014
		ADAR	CCDS 1071.1	ARHGAP5	NM 001173
A4GALT	CCDS 14041.1
		ADARB2	CCDS7058.1	ARHGAP8	CCDS 14058.1
A4GNT	CCDS3097.1
		ADCY1	NM 021116	ARHGDIG	CCDS 10404.1
AACS	CCDS9263.1
		ADCY8	CCDS6363.1	ARHGEF9	NM 015185
ABCA10	CCDS 11684.1
		ADRBK2	CCDS13832.1	ARID 1A	CCDS285.1
ABCA12	NM 015657
		AGC1	NM 001135	ARL1	NM 001177
ABCA13	NM 152701
		AGL	CCDS759.1	ARNT2	NM 014862
ABCA4	CCDS747.1
		AGPAT1	CCDS4744.1	ARP10	CCDS13985.1
ABCA5	CCDS11685.1
		AGPS	CCDS2275.1	ARSE	CCDS 14122.1
ABCA7	CCDS 12055.1
		AGRN	NM 198576	ASB4	CCDS5641.1
ABCA9	CCDS11681.1
		AHDC1	NM 001029882	ASCL4	NM 203436
ABCB1	CCDS5608.1
		AHI1	NM 017651	ASCL5	ENST00000344317
ABCB6	CCDS2436.1
		AIM1L	NM 017977	ASGR1	CCDS11089.1
ABCC10	CCDS4896.1
		AKAP11	CCDS9383.1	ASH1L	CCDS 1113.1
ABCC11	CCDS 10732.1
		AKAP13	NM 007200	AS IP	CCDS 13232.1
ABCC3	NM 003786
		AKAP4	CCDS 14329.1	ASTN	CCDS 1319.1
ABCC5	NM 005688
		AKAP9	CCDS5622.1	ATAD2B	ENST00000295142
ABCD2	CCDS 8734.1
		AKNA	CCDS6805.1	ATP10B	ENST00000327245
ABCF2	CCDS5922.1
		AKR7A2	CCDS 194.1	ATP12A	NM 001676
ABCG2	CCDS3628.1
		ALDH18A1	CCDS7443.1	ATP13A1	NM 020410
ABHD3	NM 138340
		ALDH1A2	CCDS10163.1	ATP13A2	CCDS175.1
ABHD4	CCDS9572.1
		ALDH1L1	CCDS3034.1	ATP1A2	CCDS 1196.1
ABHD7	CCDS736.1
		ALDH2	CCDS9155.1	ATP2A1	CCDS10643.1
ABL2	NM 007314
		ALLC	NM 018436	ATP2A3	CCDS11041.1
ABTB2	CCDS7890.1
		ALOX12	CCDS 11084.1	ATP2B1	CCDS9035.1
ACAD9	CCDS3053.1
		ALOXE3	CCDS11130.1	ATP2B2	CCDS2601.1
ACADS	CCDS9207.1
		ALPI	CCDS2492.1	ATP6V1G3	CCDS 1396.1
ACADSB	CCDS7634.1
		ALPK2	CCDS 11966.1	ATP7B	NM 000053
ACAT2	CCDS5268.1
		ALPK3	CCDS10333.1	ATP8A1	CCDS3466.1
ACCN1	CCDS 11276.1
		ALPL	CCDS217.1	ATP8B1	CCDS11965.1
ACCN3	CCDS5914.1
		ALS2CL	CCDS2743.1	ATRNL1	CCDS7592.1
ACF	CCDS7241.1
		ALS2CR12	CCDS2346.1	ATXN1	NM 000332
ACLY	CCDS11412.1
		AMACO	CCDS7589.1	AUTS2	CCDS5539.1
ACOX3	CCDS3401.1
		AMID	CCDS7297.1	ΑΧΙΝ2	CCDS 11662.1
ACP5	CCDS 12265.1
		ANK2	CCDS3702.1	AZI1	NM 001009811
ACRBP	CCDS 8554.1
		ANK3	CCDS7258.1	B3Gn-T6	NM 138706
ACTG1	CCDS11782.1
		ANKMY1	CCDS2536.1	BAD	CCDS 8065.1
ACINI	CCDS9792.1
		ANKRD10	CCDS9520.1	BAI2	CCDS346.1
ACTR10	NM 018477
		ANKRD11	NM 013275	BAMBI	CCDS7162.1
ACTR1A	CCDS7536.1
		ANKRD12	CCDS 11843.1	BAT2D1	CCDS 1296.1
ACTR8	CCDS2875.1
		ANKRD15	CCDS6441.1	BAZ1A	CCDS9651.1
ACTRT1	CCDS 14611.1
		ANKRD28	NM 015199	BCAR3	CCDS745.1
ADAM12	CCDS7653.1
		ANP32D	NM 012404	BCL2L1	CCDS 13188.1
ADAM15	CCDS 1084.1
		AP3B1	CCDS4041.1	BCL2L12	CCDS 12776.1
ADAM 18	CCDS6113.1
		APG7L	CCDS2605.1	BCL2L2	CCDS9591.1
ADAM28	NM 014265
		API5	NM 006595	BCL6	CCDS3289.1

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
BCOR	CCDS 14250.1	Clorfl47	NM_001025592	CACNG4	CCDS11667.1
BFSP1	CCDS13126.1	Clorfl51	NM 001032363	CADPS	CCDS2898.1
BIN1	CCDS2137.1	Clorfl6	CCDS 1355.1	CADPS2	NM_017954
BIRC1	CCDS4009.1	Clorfl73	NM_001002912	CALM1	CCDS9892.1
BIRC6	NM_016252	Clorf84	NM_015284	CAMS API	NM_015447
BMP3	CCDS3588.1	C1QDC1	CCDS 8720.1	CAPN12	CCDS 12519.1
BMPER	CCDS5442.1	C20orfl0	CCDS13352.1	CAPN3	CCDS 10084.1
BNC2	CCDS6482.1	C20orfl02	CCDS 13299.1	CAPN3	CCDS 10084.1
BOC	CCDS2971.1	C20orfl 14	CCDS13218.1	CAPZA3	CCDS 8681.1
BPY2IP1	NM018174	C20orf23	CCDS13122.1	CARD11	CCDS5336.1
BRAF	CCDS5863.1	C20orf78	ENST00000278779	CART1	CCDS9028.1
BRF1	CCDS 10001.1	C21orf29	CCDS13712.1	CASC5	NM 170589
BRP44L	CCDS5293.1	C21orf5	CCDS13643.1	CASQ1	CCDS 1198.1
BRPF1	CCDS2575.1	C21orf69	NM 058189	CCDC15	NM_025004
BSN	CCDS2800.1	C2orfl7	CCDS2434.1	CCNF	CCDS 10467.1
BST1	CCDS3416.1	C2orf29	CCDS2050.1	CCNL2	ENST00000321423
BTAF1	CCDS7419.1	C2orf3	CCDS 1961.1	CCNYL1	ENST00000339882
BTBD1	CCDS 10322.1	C3orfl4	CCDS2896.1	CD19	CCDS 10644.1
BTBD3	CCDS13113.1	C4orf7	CCDS3537.1	CD84	CCDS 1206.1
BTC	CCDS3566.1	C5AR1	NM_001736	CD96	CCDS2958.1
BTK	CCDS 14482.1	C6	CCDS3936.1	CDA08	CCDS 10728.1
BTNL2	CCDS4749.1	C6orfl03	ENST00000326929	CDC2L6	CCDS5085.1
BTNL9	CCDS4460.1	C6orfl50	CCDS4978.1	CDC7	CCDS734.1
BUCS1	CCDS10587.1	C6orfl63	NM 001010868	CDCA8	CCDS424.1
C10orfl8	ENST00000263123	C6orfl65	CCDS5009.1	CDH23	NM_022124
C10orf26	CCDS7540.1	C6orfl68	NM_032511	CDH24	CCDS9585.1
C10orf33	CCDS7474.1	C6orfl70	NM_152730	CDH26	CCDS 13485.1
C10orf47	CCDS7085.1	C6orf21	NM_001003693	CDH5	CCDS 10804.1
C10orf64	ENST00000265453	C6orf213	NM 001010852	CDK5	NM_004935
C10orf71	ENST00000323868	C6orf29	CCDS4724.1	CDK6	CCDS5628.1
C10orf80	NM_001008723	C6orf4	CCDS5092.1	CDT1	NM_030928
C10orf81	CCDS7583.1	C6orf68	CCDS5118.1	CDX1	CCDS4304.1
Cllorfll	NM 006133	C7orfl6	CCDS5436.1	CDYL2	NM_152342
C11ORF4	CCDS 8066.1	C8A	CCDS606.1	CEACAM1	CCDS 12609.1
C12orfll	CCDS 8708.1	C8B	NM 000066	CELSR3	CCDS2775.1
C12orf42	NM 198521	C8orf77	NM 001039382	CENPF	NM 016343
C14orfll5	CCDS9830.1	C8ORFK23	NM_001039112	CENTG3	NM_031946
C14orfl31	NM 018335	C9orfl26	NM 173690	CEP135	NM 025009
C14orfl33	CCDS9862.1	C9orfl9	CCDS6598.1	Cep 164	NM 014956
C14orfl45	NM_152446	C9orf5	NM_032012	CEP2	CCDS 13255.1
C14orfl55	CCDS9679.1	C9orf50	NM_199350	CETP	CCDS 10772.1
C14orfl59	NM_024952	CA2	CCDS6239.1	CFTR	CCDS5773.1
C14orf31	CCDS9704.1	CAB39	CCDS2478.1	CGI-38	CCDS 10835.1
C14orf43	CCDS9819.1	CAB INI	CCDS13823.1	CGI-96	CCDS 14036.1
C14orf49	CCDS9935.1	CABP1	CCDS9204.1	CGNL1	CCDS10161.1
C15orf2	CCDS10015.1	CACNA1A	NM_000068	CHAD	CCDS11568.1
C15orf42	ENST00000268138	CACNA1C	NM 000719	CHD4	CCDS 8552.1
C16orf9	CCDS 10402.1	CACNA1E	NM 000721	CHD5	CCDS57.1
C17orf27	NM_020914	CACNA1H	NM_021098	CHD6	CCDS13317.1
C17orf31	CCDS11016.1	CACNA1I	ΝΜ 001003406	CHD9	NM_025134
C18orf25	NM 001008239	CACNA1S	CCDS 1407.1	CHDH	CCDS2873.1
C18orf4	CCDS11995.1	CACNA2D3	NM 018398	CHEK1	CCDS 8459.1
C19orf29	ENST00000221899	CACNB2	CCDS7125.1	ChGn	CCDS6010.1

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
CHKA	CCDS8178.1	CPBl	NM_001871	DDXl	CCDS 1686.1
CHL1	CCDS2556.1	CPN1	CCDS7486.1	DDX31	CCDS6951.1
CHRM2	CCDS5843.1	CPNE2	CCDS 10774.1	DDX54	NM_024072
CHRM5	CCDS 10031.1	CPNE4	CCDS3072.1	DEFB112	NM_001037498
CHRNA3	CCDS 10305.1	CPS1	CCDS2393.1	DEFB125	CCDS 12989.1
CHRNA4	CCDS13517.1	CPSF4	CCDS5664.1	DELGEF	CCDS7828.1
CHRNA9	CCDS3459.1	CPT1B	CCDS 14098.1	DEPDC5	NM 014662
CHST13	CCDS3039.1	CPT1C	CCDS 12779.1	DFNB31	CCDS6806.1
CIDEA	CCDS 11856.1	CRA	CCDS942.1	DGCR6	CCDS13753.1
CIDEC	CCDS2587.1	CRAT	CCDS6919.1	DGKD	CCDS2504.1
CEl	CCDS6894.1	CREB1	CCDS2374.1	DHPS	CCDS 12276.1
CKLFSF5	CCDS9599.1	CRIM2	ENST00000257704	DHX29	ΝΜ 019030
CLASP1	NM_015282	CRISPLD1	CCDS6219.1	DIO3	NM_001362
CLASP2	NM 015097	CRR9	CCDS3862.1	DKFZp4341099	CCDS 10787.1
CLCN1	CCDS5881.1	CRX	CCDS 12706.1	DKFZp547A023	CCDS845.1
CLCN5	CCDS 14328.1	CRY2	CCDS7915.1	DKFZp547B1713	CCDS 1591.1
CLDN11	CCDS3213.1	CRYAA	CCDS 13695.1	DKFZP564B1023	CCDS 1403.1
CLEC1A	CCDS8612.1	CSK	CCDS 10269.1	DKFZp564I1922	CCDS14124.1
CLEC4E	CCDS 8594.1	CSMD1	NM_033225	DKFZp761L1417	CCDS5658.1
CLEC7A	CCDS8613.1	CSN3	CCDS3538.1	DKFZp761N1114	CCDS 1455.1
CLIC6	CCDS13638.1	CSNK2A2	CCDS 10794.1	DLD	CCDS5749.1
CLN8	CCDS5956.1	CSPG2	CCDS4060.1	DLEC1	ENST00000337335
CLSPN	CCDS396.1	CSPG5	CCDS2757.1	DLGAP2	NM_004745
CLSTN2	CCDS3112.1	CSPG6	NM_005445	DMN	ΝΜ 015286
CLTA	CCDS6600.1	CSTF1	CCDS 13452.1	DMTF1	CCDS5601.1
CMIP	NM 19839O	CTEN	CCDS11368.1	DNAH1	NM015512
CMYA1	CCDS2683.1	CTNNA2	NM 004389	DNAH10	CCDS9255.1
CMYA4	CCDS 11292.1	CTNNA3	CCDS7269.1	DNAH11	NM_003777
CNNM2	CCDS7543.1	CTSW	CCDS8117.1	DNAH3	CCDS 10594.1
CNOT1	CCDS 10799.1	CUBN	CCDS7113.1	DNAH5	CCDS3882.1
CNOTIO	CCDS2655.1	CUGBP1	CCDS7938.1	DNAH8	CCDS4838.1
CNOT7	CCDS6000.1	CUGBP1	CCDS7939.1	DNAH9	CCDS 11160.1
CNR2	CCDS245.1	CUL4B	NM 003588	DNAI2	CCDS11697.1
CNTN4	CCDS2558.1	CUTL1	CCDS5721.1	DNCH1	CCDS9966.1
CNTNAP2	CCDS5889.1	CX40.1	CCDS7191.1	DNCLI2	CCDS10818.1
COCH	CCDS9640.1	CXCR3	CCDS14416.1	DNHD3	NM_020877
COG5	CCDS5742.1	CXorfl7	CCDS 14356.1	DNTTIP1	CCDS 13369.1
COG5	CCDS5742.1	CXorf20	CCDS 14184.1	DOCK4	NM 014705
COH1	CCDS6280.1	CXorf27	ENST00000341016	DOCK8	CCDS6440.1
COL14A1	NM_021110	CXorf37	CCDS 14322.1	DOCK9	NM_015296
COL18A1	NM_030582	CXXC5	ΝΜ 016463	DOK6	NM_152721
COL23A1	CCDS4436.1	CYBB	CCDS 14242.1	DONSON	CCDS 13632.1
COL24A1	NM_152890	CYP26C1	CCDS7425.1	DRCTNNB1A	CCDS5377.1
COL3A1	CCDS2297.1	CYP2C19	CCDS7436.1	DRD3	CCDS2978.1
COL4A2	NM_001846	CYP2R1	CCDS7818.1	DRG1	CCDS13897.1
COL4A4	NM_000092	CYP4F12	NM_023944	DSG1	CCDS 11896.1
COL4A5	CCDS 14543.1	DAB2IP	CCDS6832.1	DSG2	NM_001943
COL5A3	CCDS 12222.1	DCBLD2	NM 080927	DSG3	CCDS 11898.1
COL6A3	NM_004369	DCC	CCDS11952.1	DSG4	CCDS 11897.1
COL6A3	NM_057167	DCT	CCDS9470.1	DSPP	NM 014208
COL8A2	CCDS403.1	DCTN4	CCDS4310.1	DST	CCDS4959.1
COPB	CCDS7815.1	DDB1	NM_001923	DTX1	CCDS9164.1
COQ2	ΝΜ 015697	DDR1	CCDS4690.1	DTX4	ENST00000227451

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
DULLARD	CCDS 11093.1	EPHA6	ENST00000334709	FLJ12700	CCDS5898.1
DUSP22	CCDS4468.1	EPHA8	CCDS225.1	FLJ13273	CCDS3672.1
DUSP3	CCDS 11469.1	EPO	CCDS5705.1	FLJ13576	CCDS5757.1
DYRK3	NM_001004023	ERCC5	NM_000123	FLJ13725	CCDS 10840.1
DZIP3	CCDS2952.1	ERF	CCDS 12600.1	FLJ13841	CCDS11819.1
E2F4	NM 001950	ERN1	NM_001433	FLJ13941	CCDS40.1
EAF1	CCDS2626.1	ESCO2	NM_001017420	FLJ14397	CCDS 1945.1
EBF	CCDS4343.1	ESPNP	ENST00000270691	FLJ16165	ΝΜ 001004318
EBF3	ΝΜ001005463	ESR1	CCDS5234.1	FLJ 16331	NM 001004326
ECEL1	CCDS2493.1	ESR2	CCDS9762.1	FLJ16478	NM_001004341
ECHDC2	CCDS571.1	ETV1	NM 004956	FLJ20035	NM_017631
ECOP	NM 030796	EVI1	CCDS3205.1	FLJ20097	ENST00000317751
EDD1	NM_015902	EVPL	CCDS11737.1	FLJ20186	CCDS 10989.1
EDG3	CCDS6680.1	EXOC6B	ENST00000272427	FLJ20232	CCDS 13995.1
EDG8	CCDS 12240.1	EXTL1	CCDS271.1	FLJ20272	NM_017735
EEF1A1	ENST00000331523	F13B	CCDS 1388.1	FLJ20294	NM_017749
EFCBP1	NM_022351	F2RL1	CCDS4033.1	FLJ20298	CCDS 14522.1
EFHC2	NM_025184	F3	CCDS750.1	FLJ21159	CCDS3792.1
EGF	CCDS3689.1	F5	CCDS 1281.1	FLJ21963	CCDS9022.1
EGFR	CCDS5514.1	FAD158	CCDS725.1	FLJ22709	CCDS 12351.1
EHBP1L1	ENST00000309295	FADS1	CCDS8011.1	FLJ23049	CCDS3199.1
EIF2A	NM_032025	FAM43A	NM_153690	FLJ23447	CCDS 12300.1
EIF3S12	CCDS 12517.1	FAM46B	CCDS294.1	FLJ23577	ENST00000303168
EIF4G1	CCDS3259.1	FAM47A	NM_203408	FLJ23577	CCDS391O.1
EIF4G2	NM_001418	FAM48A	ENST00000360252	FLJ23790	CCDS6346.1
EME2	NM 001010865	FAM63B	ΝΜ 019092	FLJ25715	NM_182570
EML4	CCDS 1807.1	FAM78B	NM 001017961	FLJ25801	CCDS385O.1
EMR4	ENST00000359590	FAM92B	NM_198491	FLJ27465	NM_001039843
EN2	CCDS5940.1	FANCA	NM 000135	FLJ30525	CCDS787.1
ENO1	CCDS97.1	FANCD2	CCDS2595.1	FLJ30655	CCDS3740.1
ENPP2	CCDS6329.1	FASN	CCDS 11801.1	FLJ30707	CCDS9427.1
ENPP6	CCDS3834.1	FAT	NM_005245	FLJ31438	NM_152385
ENPP7	CCDS 11763.1	FBN3	CCDS12196.1	FLJ32796	CCDS 1507.1
ENSA	CCDS958.1	FBXO40	NM_016298	FLJ32934	CCDS 1082.1
ENST00000294635	ENST00000294635	FBXW7	CCDS3777.1	FLJ33167	CCDS3837.1
ENST00000310882	ENST00000310882	FCGBP	CCDS 12546.1	FLJ33387	CCDS9783.1
ENST00000326382	ENST00000326382	FCHSD1	NM_033449	FLJ34512	CCDS 10424.1
ENST00000328067	ENST00000328067	FECH	CCDS11964.1	FLJ34658	CCDS3913.1
ENSTOOOOO331583	ENST00000331583	FEZ1	NM 005103	FLJ35709	CCDS7767.1
ENST00000334627	ENST00000334627	FGD1	CCDS 14359.1	FLJ35728	CCDS 1537.1
ENST00000336168	ENST00000336168	FGD4	CCDS 8727.1	FLJ36004	CCDS 8704.1
ENST00000355177	ENST00000355177	FGF2	NM 002006	FLJ36208	NM_145270
ENST00000355324	ENST00000355324	FGFR3	CCDS3353.1	FLJ36601	CCDS 14238.1
ENST00000355607	ENST00000355607	FGIF	CCDS 8300.1	FLJ37440	CCDS2095.1
ENST00000357689	ENST00000357689	FIGF	CCDS 14166.1	FLJ38964	NM_173527
ENST00000358347	ENST00000358347	FLU	CCDS 11192.1	FLJ38973	NM_153689
ENST00000359736	ENST00000359736	FLJ10276	CCDS363.1	FLJ39058	CCDS 8489.1
EPB41L2	CCDS5141.1	FLJ 10514	CCDS 1311.1	FLJ39198	NM 001039769
EPB41L4B	NM_019114	FLJ11088	CCDS8716.1	FLJ39873	CCDS2980.1
EPB49	CCDS6020.1	FLJ11535	CCDS12043.1	FLJ40243	NM_173489
EPCI	CCDS7172.1	FLJ12529	CCDS 8006.1	FLJ40342	CCDS11512.1
EPHA2	CCDS169.1	FLJ 12644	CCDS12843.1	FLJ40869	CCDS 1691.1
EPHA5	CCDS3513.1	FLJ 12671	CCDS 1153.1	FLJ41170	NM 001004332

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
FLJ41766	ENST00000338573	GBFl	CCDS7533.1	GPSl	CCDS 11800.1
FLJ43706	NM 001039774	GCGR	NM 000160	GPS2	NM_032442
FLJ44186	CCDS5854.1	GCM1	CCDS4950.1	GPSM2	CCDS792.1
FLJ44861	CCDS11778.1	GCM2	CCDS4517.1	GPT	CCDS6430.1
FLJ45300	NM 001001681	GCNT3	CCDS10172.1	GRAP2	CCDS 13999.1
FLJ45744	CCDS 12424.1	GDF3	CCDS 8581.1	GRASP	CCDS8817.1
FLJ45964	CCDS2530.1	GEFT	CCDS 8947.1	GRCA	CCDS8563.1
FLJ45974	NM 001001707	GFI1B	CCDS6957.1	GREB1	NM 014668
FLJ46072	CCDS6410.1	GFM1	NM_024996	GRIA4	CCDS8333.1
FLJ90650	CCDS4124.1	GGA2	CCDS10611.1	GRIK4	CCDS8433.1
FLT1	CCDS9330.1	GGPS1	CCDS 1604.1	GRIN2B	CCDS 8662.1
FMN2	NM 020066	GHSR	CCDS3218.1	GRIN3A	CCDS6758.1
FMNL2	NM_001004417	GIMAP1	CCDS5906.1	GRINA	NM_001009184
FN1	CCDS2399.1	GIMAP5	CCDS5907.1	GRM1	CCDS5209.1
FNBP1	NM 015033	GIMAP8	NM_175571	GRM3	CCDS5600.1
FNDC1	NM_032532	GIT2	CCDS9138.1	GSR	NM_000637
FOXA2	CCDS 13147.1	GJA4	NM 002060	GSTO2	CCDS7556.1
FOXB1	NM012182	GJB4	CCDS383.1	GTF2A2	CCDS10173.1
FOXI1	CCDS4372.1	GK	CCDS 14225.1	GTF2H4	NM_020442
FOXM1	CCDS8515.1	GLRA1	CCDS4320.1	GTF3C4	CCDS6953.1
FOXR2	NM 198451	GMCL1L	CCDS4433.1	GUCY1A3	NM 000856
FRAS1	NM_025074	GMDS	CCDS4474.1	GUCY1B2	CCDS9426.1
FREM2	NM_207361	GML	CCDS6391.1	GZMH	CCDS9632.1
FRMD3	NM_174938	GNAI2	CCDS2813.1	HAMP	CCDS 12454.1
FRMD4B	ENST00000264546	GNAT1	CCDS2812.1	HBB	NM_000519
FRMPD1	CCDS6612.1	GNL2	CCDS421.1	HBXAP	CCDS8253.1
FRMPD4	NM_014728	GNPTG	CCDS 10436.1	HCFC2	CCDS9097.1
FSD2	NM_001007122	GNS	CCDS 8970.1	HDAC2	NM_001527
FSTL1	CCDS2998.1	GOLGA3	CCDS9281.1	HDAC9	NM_178425
FSTL4	ΝΜ 015082	GOLGA4	CCDS2666.1	HDC	CCDS10134.1
FSTL5	CCDS3802.1	GORASP2	NM 015530	HECW2	NM_020760
FUBP1	CCDS683.1	GOT2	CCDS 10801.1	HERC1	NM_003922
FUT2	NM 000511	GP6	NM 016363	HERC2	CCDS 10021.1
FXYD6	CCDS8387.1	GPBP1	NM_022913	HGSNAT	ENST00000332689
FYCO1	CCDS2734.1	GPI7	CCDS3336.1	HHIP	CCDS3762.1
FZD10	CCDS9267.1	GPR114	CCDS 10785.1	HIF3A	CCDS12681.1
FZD3	CCDS6069.1	GPR116	CCDS4919.1	HIP1	NM_005338
FZD6	CCDS6298.1	GPR132	CCDS9997.1	ΗΓΥΕΡ1	NM_002114
FZD9	CCDS5548.1	GPR142	CCDS11698.1	HIVEP2	NM_006734
G3BP2	CCDS3571.1	GPR144	NM_182611	HIVEP3	CCDS463.1
GABPA	CCDS13575.1	GPR145	CCDS5044.1	HMG20A	CCDS 10295.1
GABRA6	CCDS4356.1	GPR174	CCDS 14443.1	HMGCL	CCDS243.1
GAB RD	CCDS36.1	GPR37	CCDS5792.1	HMP19	CCDS4391.1
GAD2	CCDS7149.1	GPR37L1	CCDS 1420.1	HNT	CCDS 8491.1
GALNT13	CCDS2199.1	GPR40	CCDS 12458.1	HORMAD1	CCDS967.1
GALNT3	CCDS2226.1	GPR43	CCDS 12461.1	HOXA6	CCDS5407.1
GALNT7	CCDS3815.1	GPR61	CCDS801.1	HP	NM_005143
GALNTL1	NM 020692	GPR73L1	CCDS 13089.1	HP1BP3	ΝΜ 016287
GAN AB	CCDS 8026.1	GPR74	CCDS3551.1	HPCAL4	CCDS441.1
GAPVD1	NM_015635	GPR78	CCDS3403.1	HRB	CCDS2467.1
GAS6	CCDS9540.1	GPR83	CCDS 8297.1	HRBL	CCDS5697.1
GATA4	CCDS5983.1	GPR85	CCDS5758.1	HRG	CCDS3280.1
GATA6	CCDS 11872.1	GPRC5C	CCDS11699.1	HS2ST1	CCDS712.1

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
HS2ST1	CCDS711.1	ETPR3	CCDS4783.1	KIAA0863	NM_014913
HSA9761	CCDS3981.1	IVNS1ABP	CCDS 1368.1	KIAA0980	NM_025176
HSD17B2	CCDS 10936.1	JMJD1A	CCDS 1990.1	KIAA1024	ΝΜ 015206
HSD17B8	CCDS4769.1	JMJD1B	NM_016604	KIAA1033	NM_015275
HSPA4L	CCDS3734.1	JUNB	CCDS 12280.1	KIAA1086	ENST00000262961
HSPC111	NM 016391	K0574 HUMAN	ENST00000261275	KIAA1109	ENST00000264501
HSPG2	NM_005529	KATNAL2	NM_031303	KIAA1223	NM_020337
HTR3C	CCDS3250.1	KBTBD3	CCDS 8334.1	KIAA1274	NM_014431
HTR3E	CCDS3251.1	KBTBD4	CCDS7940.1	KIAA1328	NM_020776
HXMA	CCDS10586.1	KCNA4	NM_002233	KIAA1377	NM_020802
HYPB	CCDS2749.1	KCNA7	CCDS 12755.1	KIAA1411	NM 020819
IBTK	NM_015525	KCNB2	CCDS6209.1	KIAA1441	CCDS992.1
ICAM3	CCDS 12235.1	KCNC4	CCDS821.1	KIAA1467	NM_020853
ICEBERG	NM_021571	KCND2	CCDS5776.1	KIAA1505	NM_020879
IDE	CCDS7421.1	KCNG3	CCDS 1809.1	KIAA1524	NM 020890
IDH1	CCDS2381.1	KCNH1	CCDS 1496.1	KIAA1576	NM_020927
IFI44	CCDS688.1	KCNH5	CCDS9756.1	KIAA1618	CCDS 11772.1
IFrT3	CCDS7402.1	KCNJ15	CCDS 13656.1	KIAA1754L	NM_178495
IFNAR1	CCDS 13624.1	KCNK1	CCDS 1599.1	KIAA1804	CCDS 1598.1
IFRD1	ΝΜ 001007245	KCNK5	CCDS4841.1	KIAA1862	NM_032534
IGF1	CCDS9091.1	KCNN1	NM_002248	KIAA1909	NM 052909
IGF2	CCDS7728.1	KCNQ3	NM_004519	KIAA1946	NM_177454
IGFBP7	CCDS3512.1	KCNQ4	CCDS456.1	KIAA1967	NM_021174
IGSF1	CCDS 14629.1	KCTD7	CCDS5534.1	KIAA2022	NM 001008537
IGSF10	CCDS3160.1	KCTD8	CCDS3467.1	KIAA2026	NM_001017969
IGSF9	CCDS 1190.1	KDEFR2	CCDS5351.1	KIDINS220	NM_020738
IKBKE	NM_014002	KDR	CCDS3497.1	KIFC2	CCDS6427.1
IL12RB2	CCDS638.1	KEL	NM_000420	KIFC3	CCDS 10789.1
IL17B	CCDS4297.1	KIAA0082	CCDS4835.1	KIRREL2	CCDS 12479.1
IL17RE	CCDS2589.1	KIAA0101	CCDS10193.1	KIRREL3	NM_032531
IL1F9	CCDS21O8.1	KIAA0103	CCDS6309.1	KLHDC5	NM_020782
IL1RL1	CCDS2057.1	KIAA0133	NM_014777	KFHL10	NM_152467
IL3	CCDS4149.1	KIAA0143	NM_015137	KLHL4	CCDS 14456.1
ILT7	CCDS 12890.1	KIAA0153	CCDS 14047.1	KFK9	CCDS 12816.1
MP4	CCDS2160.1	KIAA0317	NM 001039479	KEPI	CCDS 12926.1
MPDH1	NM_183243	KIAA0329	NM_014844	KLRG1	CCDS 8599.1
INDO	NM_002164	KIAA0350	NM_015226	KNTC1	NM_014708
INSIG2	CCDS2122.1	KIAA0367	NM_015225	KREMEN2	CCDS 10484.1
IPO13	CCDS503.1	KIAA0404	NM015104	KREMEN2	CCDS10483.1
IPO8	CCDS8719.1	KIAA0406	CCDS 13300.1	KRT9	NM_000226
IQGAP2	NM 006633	KIAA0528	NM_014802	KRTAP12-3	NM 198697
IQWD1	CCDS 1267.1	KIAA0649	CCDS6988.1	KRTAP20-2	CCDS 13604.1
IRS1	CCDS2463.1	KIAA0652	CCDS7921.1	KRTHA4	CCDS11390.1
IRTA2	CCDS 1165.1	KIAA0664	NM_015229	KSR1	NM_014238
IRX6	NM_024335	KIAA0672	NM_014859	L1CAM	CCDS14733.1
ISL1	NM_002202	KIAA0690	CCDS7457.1	L3MBTL2	CCDS 14011.1
ITGA4	NM 000885	KIAA0701	ΝΜ 001006947	LACE1	CCDS5067.1
ITGA7	CCDS8888.1	KIAA0703	NM 014861	LACRT	CCDS8883.1
ITGAL	NM_002209	KIAA0748	ENST00000316577	LAMA1	NM_005559
FTGAX	CCDS 10711.1	KIAA0759	CCDS9852.1	LAM A3	CCDS 11880.1
ΓΓΙΗ5	NM_032817	KIAA0774	NM 001033602	LAMA4	NM 002290
ΓΓΕΝ1	CCDS 1211.1	KIAA0802	CCDS 11841.1	LAMB3	CCDS 1487.1
ITPKB	CCDS 1555.1	KIAA0831	NM 014924	LAMP3	CCDS3242.1

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
LAP1B	CCDS 1335.1	LOC648272	ENST00000343945	MAN1B1	CCDS7029.1
LARGE	CCDS13912.1	LOC651746	ENST00000296657	MAN2A1	NM_002372
LARP5	NM_015155	LOC651863	ENST00000333744	MAN2B1	NM 000528
LATS1	NM_004690	LOC90379	NM_138353	MAP1B	CCDS4012.1
LATS2	CCDS9294.1	LOC90826	CCDS3771.1	MAP3K11	CCDS8107.1
LAX	CCDS 1441.1	LOC92154	NM_138383	MAP3K14	NM_003954
LBP	CCDS13304.1	LOC93349	NM_138402	MAP3K8	CCDS7166.1
LCA10	NM 001039768	LPAL2	ENST00000342479	MAP3K9	NM_033141
LCT	CCDS2178.1	LPHN1	CCDS 12307.1	MAP4K4	NM_004834
LDLRAD3	NM_174902	LPHN2	CCDS689.1	MAP7D3	ENST00000218318
LEMD2	CCDS4785.1	LPHN3	NM_015236	MARCO	CCDS2124.1
LENG8	CCDS 12894.1	LPIN3	NM 022896	MARK3	NM_002376
LETM1	CCDS3355.1	LPL	CCDS6012.1	MARS	CCDS 8942.1
LETMD1	CCDS 8806.1	LRAT	CCDS3789.1	MARS2	NM_138395
LIP8	CCDS 11126.1	LRCH1	NM015116	MASS1	NM 032119
LIPM	ENST00000282673	LREN5	CCDS9678.1	MAST4	ENST00000261569
LMNB1	CCDS4140.1	LRP1	CCDS 8932.1	MATN1	CCDS336.1
LMX1A	CCDS 1247.1	LRP10	CCDS9578.1	MBD1	CCDS11941.1
LNX	CCDS3492.1	LRP1B	CCDS2182.1	MBNL1	CCDS3163.1
LNX2	CCDS9323.1	LRP2	CCDS2232.1	MCCC1	CCDS3241.1
LOCI 13655	CCDS6431.1	LRRC16	NM_017640	MCF2L	ENST00000261963
LOCI 24842	CCDS 11283.1	LRRC4	CCDS5799.1	MCFD2	NM_139279
LOCI 26248	CCDS 12429.1	LRRC4B	ENST00000253728	MCM10	CCDS7095.1
LOC131368	CCDS2947.1	LRRC7	CCDS645.1	MCPH1	NM_024596
LOC131873	ENST00000358511	LRRIQ1	NM_032165	MDGA1	NM_153487
LOCI 34145	NM_199133	LRRK1	NM_024652	MDH2	CCDS5581.1
LOC146562	CCDS 10521.1	LRRN1	NM_020873	MEA	CCDS4879.1
LOC158830	NM_001025265	LRRN3	CCDS5754.1	MED12	NM_005120
LOC200312	NMOO1O17981	LRRN5	CCDS 1448.1	MEFV	CCDS 10498.1
LOC221955	CCDS5350.1	LTB4R2	CCDS9624.1	MEN1	CCDS8083.1
LOC257106	CCDS 1215.1	LTBP1	NM_000627	METTL5	NM_014168
LOC283537	CCDS9332.1	LTBP3	CCDS8103.1	MGAM	NM 004668
LOC284912	CCDS13918.1	LTBP4	NM_003573	MGC16635	CCDS 14097.1
LOC284948	CCDS 1976.1	LTK	CCDS 10077.1	MGC19764	NM_144975
LOC339977	ΝΜ 001024611	LUC7L	CCDS 10401.1	MGC20419	CCDS562.1
LOC374768	NM 199339	LY6K	CCDS6385.1	MGC20741	CCDS4861.1
LOC387755	NM_001031853	LYNX1	ENST00000317543	MGC21830	CCDS10463.1
LOC387856	NM 001013635	LYPLA1	CCDS6157.1	MGC24039	NM_144973
LOC388595	NM 001013641	LYRIC	CCDS6274.1	MGC2655	CCDS10491.1
LOC388969	NM_001013649	LYST	NM_000081	MGC26598	CCDS9036.1
LOC391123	NM 001013661	LYZL4	CCDS2697.1	MGC26818	CCDS44.1
LOC392617	ENST00000333066	LZTR2	NM_033127	MGC27016	CCDS3790.1
LOC400707	NM_001013673	M160	CCDS 8577.1	MGC29814	CCDS 11742.1
LOC441136	NMOO1O13719	MACL1	CCDS435.1	MGC29875	CCDS 1493.1
LOC441233	NM 001013724	MAEA	NM 001017405	MGC33367	CCDS 10738.1
LOC442213	NM_001013732	MAGEA4	CCDS 14702.1	MGC33414	CCDS279.1
LOC494115	ΝΜ001008662	MAGEB10	NM 182506	MGC33486	CCDS8133.1
LOC51058	CCDS476.1	MAGEC1	NM_005462	MGC33889	CCDS14216.1
LOC54103	NM_017439	MAGEH1	CCDS 14369.1	MGC34647	CCDS 10895.1
LOC54499	CCDS 1251.1	MAGI-3	CCDS859.1	MGC35118	CCDS 10046.1
LOC550631	NM 001017437	MAK10	CCDS6673.1	MGC35194	CCDS147.1
LOC63928	CCDS10617.1	MALT1	CCDS11967.1	MGC35366	CCDS9057.1
LOC643866	NM 001039771	MAMDC2	CCDS6631.1	MGC39581	CCDS12149.1

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
MGC42174	NM_152383	MYBPC3	NM_000256	NLGN2	CCDSll 103.1
MGC4251	CCDS 11474.1	MYBPHL	NM 001010985	NLN	CCDS3989.1
MGC4268	CCDS2152.1	MYF6	CCDS9019.1	ΝΜ 001080470.1	ENST00000271263
MGC45562	CCDS11371.1	MYH14	NM_024729	NMBR	CCDS5196.1
MGC45780	CCDS6064.1	MYH15	ENST00000273353	NMUR1	CCDS2486.1
MGC47869	CCDS 8667.1	MYH3	CCDS11157.1	NNT	CCDS3949.1
MHC2TA	CCDS 10544.1	MYH4	CCDS 11154.1	NOD3	NM_178844
MIA3	ENST00000320831	MYO15A	ΝΜ 016239	NOR1	CCDS409.1
MICAL-L2	CCDS5324.1	MYO18B	NM 032608	NOS3	CCDS5912.1
MINK1	NM_170663	MYO1B	CCDS2311.1	NOTCH1	NM_017617
MIPEP	CCDS9303.1	MYOID	NM_015194	NOTCH2	CCDS908.1
MIR16	CCDS 10578.1	MYO1E	NM 004998	NOTCH3	CCDS 12326.1
MKI67	CCDS7659.1	MYO3A	CCDS7148.1	NOTCH4	NM_004557
MLL	NM_005933	MYO3B	NM 138995	NOX4	CCDS 8285.1
MLL3	CCDS5931.1	MYO5A	NM 000259	NP 001073909.1	ENST00000327928
MLL4	NM_014727	MYO5C	NM_018728	NP_001073931.1	ENST00000341689
MLLT4	CCDS5303.1	MYO9B	NM_004145	NP 001073940.1	ENST00000292357
MLLT7	NM 005938	MYOCD	CCDS11163.1	NP 001073948.1	ENST00000296794
MME	CCDS3172.1	MYOM1	NM_003803	NP_001073961.1	ENST00000219301
MMP10	CCDS8321.1	MYOM2	CCDS5957.1	NP_001073971.1	ENST00000266524
MMP16	CCDS6246.1	MYR8	NM015011	NP 001074294.1	ENST00000342607
MOCS1	CCDS4845.1	MYRIP	CCDS2689.1	NPC1L1	CCDS5491.1
MON2	ΝΜ 015026	MYST3	CCDS6124.1	NPL	CCDS 1350.1
MPDU1	CCDS11115.1	MYT1L	NM_015025	NPLOC4	NM_017921
MPDZ	NM_003829	NAGA	CCDS 14030.1	NPPA	CCDS139.1
MPP1	CCDS 14762.1	NALP1	NM_014922	NPR3	NM 000908
MPZ	CCDS 1229.1	NALP11	CCDS 12935.1	NPTXR	NM_014293
MRC2	CCDS 11634.1	NALP7	CCDS 12912.1	NR_002781.1	ENST00000246203
MRGX1	CCDS7846.1	NAPSB	ENST00000253720	NR2E1	CCDS5063.1
MRPL13	CCDS6332.1	NARG1L	CCDS9379.1	NRAP	CCDS7578.1
MRPL16	CCDS7976.1	NAVI	CCDS 1414.1	NRBP2	NM_178564
MRPL37	ENST00000329505	NCBP1	CCDS6728.1	NRK	NM 198465
MRPL44	CCDS2459.1	NCKAP1L	NM_005337	NRP1	CCDS7177.1
MRPL46	CCDS 10341.1	NCOA5	CCDS 13392.1	NRP2	CCDS2364.1
MRPL55	CCDS 1567.1	NCOA6	CCDS 13241.1	NRXN2	CCDS 8077.1
MRPS5	CCDS2010.1	NDUFA11	CCDS12155.1	NS3TP2	CCDS4136.1
MRPS7	CCDS11718.1	NDUFB2	CCDS5862.1	NT5E	CCDS5002.1
MR VII	NM 006069	NDUFS6	CCDS3866.1	NTN2L	CCDS 10469.1
MS4A7	CCDS7985.1	NEB	NM_004543	NTRK3	CCDS 10340.1
MSI2	CCDS11596.1	NEIL3	CCDS3828.1	NUAK1	NM_014840
MSL2L1	NM018133	NEUROG2	CCDS3698.1	NUP160	NM_015231
MSRB3	CCDS8973.1	NF1	CCDS 11264.1	NUP188	NM_015354
MTA1	NM_004689	NFATC3	CCDS 10862.1	NUP205	NM_015135
MTHFD2L	ΝΜ 001004346	NFATC4	CCDS9629.1	NUP210L	NM_207308
MTNR1B	CCDS 8290.1	NGEF	CCDS2500.1	NUP98	CCDS7746.1
MTP	CCDS3651.1	NHS	CCDS14181.1	NURIT	CCDS9399.1
MTR	CCDS 1614.1	NIF3L1BP1	CCDS29OO.1	NXF3	CCDS14503.1
MTX2	CCDS2272.1	NIN	NM_182944	NXF5	CCDS 14491.1
MUC15	CCDS7859.1	NISCH	NM_007184	NXPH1	NM_152745
MUC16	NM_024690	NKG7	CCDS 12830.1	OAS3	NM 006187
MUC5AC	ENST00000349637	NKRF	NM_017544	OBSCN	CCDS 1570.1
MUC7	CCDS3541.1	NKX2-5	CCDS4387.1	ODZ2	ENST00000314238
MVP	CCDS 10656.1	NLGN1	CCDS3222.1	OLIG2	CCDS 13620.1

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
OPRDl	CCDS329.1	OR9Q2	NM_001005283	PDZD7	NM_024895
OPRL1	CCDS13556.1	OSAP	NM_032623	PEG10	ENST00000362013
OR10G3	ΝΜ001005465	OSBPL2	CCDS 13494.1	PELP1	NM_014389
OR10G4	NM_001004462	OSBPL5	NM_145638	PENK	CCDS6168.1
OR10H2	CCDS12333.1	OSBPL9	CCDS558.1	PERQ1	NM_022574
OR10P1	NM 206899	OSR2	NMO53OO1	PEX1	CCDS5627.1
OR10T2	NM_001004475	OSTM1	CCDS5062.1	PEX10	CCDS41.1
OR 13 J1	ΝΜ 001004487	OTOF	CCDS 1725.1	PFAS	CCDS11136.1
OR1L8	ΝΜ 001004454	OTOG	ENST00000342528	PFKFB3	CCDS7078.1
OR2A12	NM_001004135	OTOR	CCDS13124.1	PGAP1	CCDS2318.1
OR2AG1	ΝΜ 001004489	OTUD1	ENST00000298035	PGBD5	CCDS 1583.1
OR2AG2	ΝΜ 001004490	OVCH1	NM_183378	PHC3	NM_024947
OR2D2	NM_003700	OVOL1	CCDS8112.1	PHEMX	CCDS7733.1
OR2G3	NM 001001914	OXA1L	CCDS9573.1	PHF2	ENST00000298216
OR2L13	CCDS 1637.1	p44S10	CCDS2901.1	PHF21A	NM 016621
OR2L2	NM_001004686	PAD 12	CCDS177.1	PHIP	CCDS4987.1
OR2S2	CCDS6596.1	PAPLN	NM_173462	PHKA2	CCDS 14190.1
OR2T4	ΝΜ 001004696	PAPOLG	CCDS 1863.1	PHLPP	NM_194449
OR2V2	CCDS4461.1	PAPPA2	NM_020318	PHLPPL	NM_015020
OR2Y1	NM 001001657	PARC	CCDS4890.1	PHOX2B	CCDS3463.1
OR2Z1	ΝΜ 001004699	PARP11	CCDS8523.1	PIGN	NM_176787
OR3A1	CCDS 11023.1	PAX9	CCDS9662.1	PIGQ	CCDS10411.1
OR4A5	ΝΜ 001005272	PCAF	CCDS2634.1	PIGR	CCDS 1474.1
OR4L1	ΝΜ 001004717	PCDH1IX	CCDS 14463.1	PK3C2G	NM_004570
OR4N2	NM_001004723	PCDHA10	NM_031859	PIK3CA	NM_006218
OR4P4	NM 001004124	PCDHA13	CCDS4240.1	PIK3CG	CCDS5739.1
OR52A5	ΝΜ001005160	PCDHB7	CCDS4249.1	PIK3R1	CCDS3993.1
OR52B2	NM_001004052	PCDHGA4	NM_032053	PIK3R4	CCDS3067.1
OR52D1	ΝΜ 001005163	PCDHGA9	NM_032089	PIK3R5	CCDS 11147.1
OR52E6	ΝΜ001005167	PCDHGB7	NM 032101	PIP5K1A	CCDS990.1
OR52I1	NM_001005169	PCDHGC4	CCDS4260.1	PIP5K3	CCDS2382.1
OR52N4	ΝΜ 001005175	PCDHGC4	CCDS4261.1	PISD	CCDS13899.1
OR56A4	ΝΜ 001005179	PCDHGC4	CCDS4263.1	ΡΓΓΡΝΜ1	NM 004910
OR56B1	NM_001005180	PCGF2	NM_007144	ΡΓΓΡΝΜ2	CCDS9242.1
OR56B4	NMOO1OO5181	PCNXL2	ENST00000344698	ΡΓΓΡΝΜ3	CCDS 11076.1
OR5A1	ΝΜ 001004728	PCSK2	CCDS13125.1	PIWIL3	ΝΜ 001008496
OR5AP2	NM_001002925	PCYOX1	CCDS 1902.1	PKD1	NM_000296
OR5AU1	ΝΜ 001004731	PDCD10	CCDS3202.1	PKD1L2	NM_182740
OR5B17	ENST00000357377	PDCD11	NM_014976	PKHD1	CCDS4935.1
OR5BF1	NM_OO1OO1918	PDE1C	CCDS5437.1	PKHD1L1	NM_177531
OR5D14	NM 001004735	PDE4A	CCDS 12238.1	PKIA	CCDS6222.1
OR5K4	ΝΜ 001005517	PDE4B	CCDS632.1	PLA1A	CCDS2991.1
OR5M1	ENSTOOOOO3O3OO5	PDE4C	CCDS12373.1	PLCH2	NM_014638
OR5M8	ΝΜ 001005282	PDE4D	NM 006203	PLCXD3	ΝΜ 001005473
OR5M9	ΝΜ 001004743	PDGFB	CCDS13987.1	PLD2	CCDS11057.1
OR6C74	NM_001005490	PDGFRA	CCDS3495.1	PLEC1	NM_201378
OR6K3	NM 001005327	PDGFRB	CCDS4303.1	PLEKHA4	CCDS 12737.1
OR6W1P	ENST00000340373	PDHA2	CCDS3644.1	PLEKHH2	CCDS1812.1
OR7A5	CCDS12318.1	PDHB	CCDS2890.1	PLZN	CCDS10353.1
OR7D4	NMOO1OO5191	PDIA2	NM 006849	PLSCR3	NM 020360
OR8D2	ΝΜ 001002918	PDK1	CCDS2250.1	PLXDC2	CCDS7132.1
OR8K3	NM_001005202	PDLIM4	CCDS4152.1	PLXNA3	CCDS 14752.1
OR9K2	NM 001005243	PDZD2	NM 178140	PLXNB2	ENST00000359337

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
PLXNCl	CCDS9049.1	PSRC2	NM_144982	Q96CK5_HUMAN	ENST00000273582
PMS1	CCDS2302.1	PTAR1	ENST00000340434	Q96DR3HUMAN	ENST00000324748
PMS2L4	ENST00000275546	PTCH2	CCDS516.1	Q96EF7HUMAN	ENST00000269720
PNLIP	CCDS7594.1	PTEN	NM_000314	Q96NE0_HUMAN	ENST00000329922
PNOC	CCDS6066.1	PTGDR	CCDS9707.1	Q96NL2HUMAN	ENST00000272907
PODXL2	CCDS3044.1	PTGFR	CCDS686.1	Q96PS2HUMAN	ENST00000326978
POLD1	CCDS 12795.1	PTGS2	CCDS 1371.1	Q9H030_HUMAN	ENST00000237449
POLE	CCDS9278.1	PTPLA	CCDS7121.1	Q9H6A9_HUMAN	ENST00000309024
POLG2	NM_007215	PTPN23	CCDS2754.1	Q9H8OOHUMAN	ENST00000357106
POLM	NM_013284	PTPRF	CCDS489.1	Q9H8D1_HUMAN	ENST00000360549
POLR3B	CCDS9105.1	PTPRK	CCDS5137.1	Q9HAC4HUMAN	ENST00000206466
POLR3E	CCDS 10605.1	PTPRM	CCDS 11840.1	Q9P1M5HUMAN	ENST00000303007
POPDC2	CCDS2992.1	PTPRS	CCDS12139.1	Q9UEE4_HUMAN	ENST00000265018
POR	CCDS5579.1	PTPRU	CCDS334.1	Q9Y6V0-3	ENST00000333891
PORCN	CCDS 14296.1	PTX3	CCDS3180.1	QPCT	CCDS 1790.1
POT1	CCDS5793.1	PUM1	CCDS338.1	QRICH2	NM_032134
POU1F1	CCDS2919.1	PYGB	CCDS13171.1	QSCN6	CCDS 1337.1
POU2F1	CCDS 1259.1	Q13034 HUMAN	ENST00000225928	QSER1	NM_024774
POU6F2	NM_007252	Q4VXG5_HUMAN	ENST00000327794	QTRTD1	NM_024638
PPAP2C	CCDS12023.1	Q4VXG5HUMAN	ENST00000331811	RAB36	CCDS13805.1
PPARA	NM 001001930	Q5JX50HUMAN	ENST00000325076	RAB3C	CCDS3976.1
PPBP	CCDS3563.1	Q5JYU7_HUMAN	ENST00000333418	RAB3GAP2	NM_012414
PPEE2	NM 006239	Q5T740 HUMAN	ENST00000343319	RAB3IL1	CCDS8014.1
PPIG	CCDS2235.1	Q5W0A0HUMAN	ENST00000298738	RAC2	CCDS 13945.1
PPL	CCDS 10526.1	Q68CJ6_HUMAN	ENST00000341513	RAD23A	CCDS 12289.1
PPM2C	CCDS6259.1	Q6IEE8_HUMAN	ENST00000354872	RAD51L3	CCDS11287.1
PPP1CC	CCDS9150.1	Q6PK04HUMAN	ENST00000329214	RAD52	CCDS 8507.1
PPP1R12A	NM_002480	Q6RGF6_HUMAN	ENST00000359144	RAFTLIN	NM_015150
PPP1R12C	CCDS 12916.1	Q6ZRB0HUMAN	ENST00000297487	RAI1	CCDS11188.1
PPP2CZ	CCDS855.1	Q6ZSY1_HUMAN	ENST00000320930	RALBP1	CCDS 11845.1
PPP2R2C	CCDS3387.1	Q6ZT40_HUMAN	ENST00000296564	RANBP17	NM_022897
PPRC1	CCDS7529.1	Q6ZUG5HUMAN	ENST00000344062	RANP1	ENST00000333828
PRCC	CCDS 1157.1	Q6ZV46HUMAN	ENST00000341696	RAP140	CCDS2877.1
PRDM16	NM_199454	Q76B6I IICYIAN	ENST00000360022	RAPGEF4	NM_007023
PRDM5	CCDS3716.1	Q86U37HUMAN	ENST00000335192	RAPGEF6	ΝΜ 016340
PRELP	CCDS 1438.1	Q86XQ1_HUMAN	ENST00000261673	RAPGEFL1	CCDS11363.1
PRIC285	CCDS 13527.1	Q86YU6_HUMAN	ENST00000330768	RAPH1	CCDS2359.1
PRKCBP1	CCDS 13404.1	Q8IUR1HUMAN	ENST00000327506	RARSL	CCDS5011.1
PRKCZ	CCDS37.1	Q8N1R6HUMAN	ENST00000331014	RASGRF1	CCDS 10309.1
PRKDC	NM_006904	Q8N646_HUMAN	ENST00000359720	RASGRF2	CCDS4052.1
PRKG2	CCDS3589.1	Q8N8OOHUMAN	ENST00000322516	RASL11B	CCDS3490.1
PRKRA	CCDS2279.1	Q8N822_HUMAN	ENST00000317280	RAX	CCDS 11972.1
PRO 1853	CCDS 1788.1	Q8N8C3_HUMAN	ENST00000319889	RBI	NM_000321
PRO 1855	CCDS11566.1	Q8N8K0HUMAN	ENST00000301807	RBM14	CCDS 8147.1
PROM1	NM 006017	Q8N9H1_HUMAN	ENST00000359503	RBM19	CCDS9172.1
PROSC	CCDS6096.1	Q8NBE0_HUMAN	ENST00000297801	RBM21	CCDS8021.1
PRPF18	CCDS7100.1	Q8NDH2HUMAN	ENST00000322527	RBM25	NM_021239
PRR12	ENST00000246798	Q8NGK8HUMAN	ENST00000334020	RBM27	ENST00000265271
PRSS16	CCDS4623.1	Q8NGL5_HUMAN	ENST00000328673	RBM34	ENST00000362051
PRSS22	CCDS10481.1	Q8NH06HUMAN	ENST00000324144	RBMS3	ΝΜ 001003792
PSF1	NM_021067	Q8NHB0HUMAN	ENST00000315712	RBP3	CCDS7218.1
PSIP1	CCDS6479.1	Q8TBR1_HUMAN	ENST00000354206	RBPSUH	CCDS3436.1
PSMD8	CCDS 12515.1	Q96CH6HUMAN	ENST00000329920	RC74	ΝΜ 018250

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
RCD-8	CCDS 10849.1	SARG	CCDS 1475.1	SIPA1L2	NM_020808
RDHE2	CCDS6167.1	SARS	CCDS795.1	SIPA1L3	NM_015073
RDS	CCDS4871.1	SASH1	CCDS5212.1	SKIV2L	CCDS4731.1
REGIB	CCDS 1963.1	SCHIP1	CCDS3186.1	SKP2	CCDS3915.1
REN	NM_000537	SCN1B	CCDS 12441.1	SLC10A4	CCDS3482.1
REPS2	CCDS 14180.1	SCN3A	NM 006922	SLC11A1	CCDS2415.1
RET	CCDS7200.1	SCN3B	CCDS 8442.1	SLC12A1	CCDS10129.1
RFC2	CCDS5567.1	SCN5A	NM 000335	SLC12A5	CCDS13391.1
RFNG	NM_002917	SCN9A	NM_002977	SLC14A1	CCDS11925.1
RFX3	CCDS6450.1	SCRIB	CCDS6411.1	SLC14A2	CCDS 11924.1
RGS22	ΝΜ 015668	SCUBE1	CCDS 14048.1	SLC16A5	CCDS11713.1
RGSL1	CCDS 1346.1	SDC3	NM_014654	SLC1A2	NM_004171
RHOT1	NM_001033568	SDR-O	CCDS 8926.1	SLC22A11	CCDS 8074.1
RICTOR	NM_152756	SEC24C	CCDS7332.1	SLC22A18	CCDS7740.1
RIMBP2	NM_015347	SELO	NM_031454	SLC22A3	CCDS5277.1
RIMS2	NM_014677	SEMA5A	CCDS3875.1	SLC24A6	NM_024959
RIMS4	CCDS13338.1	SEMA5B	CCDS3019.1	SLC25A13	CCDS5645.1
RIPK4	CCDS 13675.1	SEMA7A	CCDS 10262.1	SLC26A4	CCDS5746.1
RLBP1	NM_000326	SEN2L	CCDS2611.1	SLC2A1	CCDS477.1
RLTPR	NMOO1O13838	SENP3	ΝΜ 015670	SLC30A1	CCDS 1499.1
RNASEH2A	CCDS 12282.1	SEPT2	CCDS2548.1	SLC30A5	CCDS3996.1
RNF103	NM_005667	SERPINA12	CCDS9926.1	SLC30A9	CCDS3465.1
RNF127	CCDS 14575.1	SERPINA9	NM_175739	SLC35B2	NM_178148
RNF128	CCDS 14521.1	SERPINB3	CCDS11987.1	SLC35D3	NM 001008783
RNF19	CCDS6286.1	SERPINB7	CCDS11988.1	SLC35F2	NM_017515
RNF25	CCDS2420.1	SERPINE2	CCDS2460.1	SLC38A1	NM_030674
RNF40	CCDS10691.1	SERPING1	CCDS7962.1	SLC38A4	CCDS 8750.1
RNPC2	CCDS 13265.1	SET7	CCDS3748.1	SLC38A6	CCDS9751.1
ROBO3	NM_022370	SETDB2	CCDS9417.1	SLC39A2	CCDS9563.1
ROCK1	CCDS 11870.1	SEZ6	NM_178860	SLC43A3	CCDS7956.1
ROM1	CCDS 8024.1	SEZ6L	CCDS13833.1	SLC4A1	CCDS11481.1
ROS1	CCDS5116.1	SFI1	ΝΜ001007467	SLC4A5	CCDS 1936.1
RoXaN	CCDS14013.1	SFMBT2	NM 001029880	SLC4A7	NM 003615
RP1L1	NM_178857	SFRP2	NM_003013	SLC5A5	CCDS 12368.1
RPL11	CCDS238.1	SFTPB	CCDS 1983.1	SLC5A7	CCDS2074.1
RPS14	CCDS4307.1	SG223 HUMAN	ENST00000330777	SLC7A10	CCDS 12431.1
RPS6KA2	CCDS5294.1	SGCZ	CCDS5992.1	SLC7A13	NM_138817
RPS6KB2	NM_003952	SGK2	CCDS 13320.1	SLC7A14	NM_020949
RPUSD3	CCDS2586.1	SGPP1	CCDS9760.1	SLC7A6	NM 003983
RRAGD	CCDS5022.1	SGPP2	CCDS2453.1	SLC8A1	CCDS 1806.1
RSHL1	CCDS 12675.1	SGSH	CCDS 11770.1	SLC9A1	CCDS295.1
RSU1	CCDS7112.1	SH3BP1	CCDS 13952.1	SLC9A2	CCDS2062.1
RTN1	CCDS9740.1	SH3BP2	NM_003023	SLC9A3R2	NM_004785
RTTN	NM_173630	SH3GL3	CCDS 10325.1	SLC9A4	NM 001011552
RUNX1	CCDS 13639.1	SHANK2	CCDS8198.1	SLCO1B1	CCDS 8685.1
RUNX1T1	CCDS6256.1	SHANK3	ENST00000262795	SLCO2A1	CCDS3084.1
RWDD1	ΝΜ001007464	SHB	NM 003028	SLCO4C1	NM 180991
RYR2	NM_001035	SHE	NM 001010846	SLCO6A1	NM_173488
RYR3	NM_001036	SHMT2	CCDS 8934.1	SLIT2	CCDS3426.1
SALL3	CCDS12013.1	SIGLEC11	CCDS 12790.1	SLTTRK1	CCDS9464.1
SAMD11	ENST00000294573	SIGLEC5	NM 003830	SLTTRK5	CCDS9465.1
SAMD9	NM_017654	SIGLEC8	NM_014442	SL1TRK6	ENST00000313206
SAPS2	NM 014678	SIM2	CCDS 13646.1	SMARCA2	NM 003070

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
SMARCA4	CCDS12253.1	STAP2	CCDS12128.1	TGFBRAPl	CCDS2067.1
SMARCC2	CCDS 8907.1	STIM2	CCDS3440.1	TGM1	CCDS9622.1
SMC5L1	CCDS6632.1	STK33	CCDS7789.1	TGM5	NM_004245
SMCR8	CCDS11195.1	STK39	NM_013233	THAP9	CCDS3598.1
SMFHUMAN	ENST00000261804	STRA6	CCDS 10261.1	THBS1	NM_003246
SN	CCDS 13060.1	STS	CCDS14127.1	THEA	CCDS592.1
SNED1	ENST00000310397	STS-1	NM_032873	THOP1	CCDS 12095.1
SNRPA	CCDS 12565.1	STX11	CCDS5205.1	THRAP3	ENST00000354618
SNX13	NM_015132	STX12	CCDS310.1	THSD7B	ENST00000272643
SNX27	CCDS 1001.1	STXBP2	CCDS12181.1	TIMP2	CCDS11758.1
SNX4	CCDS3032.1	STXBP3	CCDS790.1	TINAG	CCDS4955.1
SOCS5	CCDS 1830.1	STYK1	CCDS 8629.1	TJP3	NM_014428
SOHLH1	NM_001012415	SUCLA2	CCDS9406.1	TLL1	CCDS3811.1
SORCS2	NM_020777	SUCLG2	NM_003848	TLN1	NM 006289
SORCS3	CCDS7558.1	SULT6B1	NM 001032377	TLX3	NM_021025
SORL1	CCDS 8436.1	SUNC1	NM_152782	TM4SF14	CCDS7369.1
SOS1	CCDS 1802.1	SUSD5	ENST00000309558	TM4SF3	CCDS 8999.1
SOSTDC1	CCDS5360.1	SV2B	CCDS 10370.1	TM9SF4	CCDS13196.1
SOX13	NM_005686	SWAP70	NM_015055	TMED1	CCDS 12249.1
SOX30	CCDS4339.1	SYDE2	ENST00000234668	TMEM131	ENST00000186436
SOX8	CCDS 10428.1	SYN2	NM_133625	TMEM132C	ENST00000315208
SP100	CCDS2477.1	SYNE1	CCDS5236.1	TMEM16B	NM_020373
SPACA4	CCDS 12725.1	SYNE1	CCDS5237.1	TMEM16C	NM_031418
SPAG1	NM_003114	SYNE2	CCDS9761.1	TMEM16E	NM_213599
SPAG5	NM_006461	SYT15	NM_181519	TMEM16G	NM_001001891
SPAG7	NM 004890	SYT16	NM_031914	TMEM16J	NM 001012302
SPATA1	CCDS697.1	SYT6	CCDS871.1	TMEM38A	CCDS 12349.1
SPATA2	CCDS 13422.1	TAAR9	ENST00000340640	TMEM46	NM_OO1OO7538
SPATC1	CCDS6413.1	TACC2	CCDS7626.1	TMEM63B	ΝΜ 018426
Spc25	CCDS2229.1	TACC3	CCDS3352.1	TMEM8	CCDS 10407.1
SPEG	ENST00000265327	TAF1L	NM_153809	TMPRSS2	NM_005656
SPEN	CCDS 164.1	TAF4B	ENST00000269142	TMPRSS4	ΝΜ 019894
SPG3A	CCDS9700.1	TAF6	CCDS5686.1	TNC	CCDS6811.1
SPI1	CCDS7933.1	TANC1	NM_033394	TNFAIP2	CCDS9979.1
SPIN3	NM 001010862	TAOK1	NM 020791	TNFSF18	CCDS 1305.1
SPIRE2	NM_032451	TARBP2	CCDS8861.1	TNFSF4	CCDS 1306.1
SPN	CCDS 10650.1	TAS1R2	CCDS187.1	TNFSF9	CCDS12169.1
SPOCK3	ΝΜ 016950	TAS2R3	CCDS5867.1	TNIP1	NM 006058
SPON2	CCDS3347.1	TBC1D20	CCDS 13002.1	TNIP2	CCDS3362.1
SPRED2	NM_181784	TBC1D4	NM_014832	TNK1	NM_003985
SPTB	ΝΜ001024858	TBCD	NM 001033052	TNMD	CCDS 14469.1
SPTBN1	NM 178313	TBX20	CCDS5445.1	TNN	NM_022093
SPTBN2	CCDS8150.1	TBX22	CCDS 14445.1	TNPO1	CCDS4016.1
SPTBN4	CCDS 12559.1	TCF7L1	CCDS 1971.1	TNR	CCDS1318.1
SPTBN5	NM_016642	TCF8	CCDS7169.1	TNRC15	NM_015575
SREBF2	CCDS 14023.1	TCHH	ENST00000290632	TNRC4	CCDS 1002.1
SRGAP1	CCDS 8967.1	TCN2	CCDS13881.1	TNRC6C	ΝΜ 018996
SRPK2	CCDS5735.1	TDRD5	CCDS 1332.1	TOE1	CCDS521.1
SRRM2	NM_016333	TDRD9	CCDS9987.1	TOP2A	NM_001067
SSFA2	CCDS2284.1	TEAD2	CCDS 12761.1	TOR1A	CCDS6930.1
STM	CCDS 8487.1	TEPP	CCDS 10790.1	TOSO	CCDS 1473.1
ST8SLA4	CCDS4091.1	TERF2IP	NM_018975	TP53	CCDS11118.1
STAB1	NM 015136	TFE3	CCDS 14315.1	TPH2	NM 173353

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Gene symbol	Accession ID	Gene symbol	Accession ID	Gene symbol	Accession ID
TPR	NM_003292	UNQ689	CCDS3542.1	ZAN	NM_173059
TPST2	CCDS13839.1	UPK3B	CCDS5588.1	ZBTB16	CCDS 8367.1
TRAM 1 LI	CCDS3707.1	URB1	ENST00000270201	ZBTB24	NM_014797
TRAPPC3	CCDS404.1	USH2A	CCDS 1516.1	ZBTB4	CCDS11107.1
TREML2	CCDS4853.1	USP 11	CCDS 14277.1	ZBTB9	NM_006772
TREML3	ENST00000332842	USP26	CCDS 14635.1	ZC3H6	NM 198581
TRIM14	CCDS6734.1	USP8	CCDS10137.1	ZFPM1	NM_153813
TRIM42	CCDS3113.1	VANGL1	CCDS883.1	ZFYVE9	CCDS563.1
TRIM45	CCDS893.1	VCAM1	CCDS773.1	ZIC1	CCDS3136.1
TRIM46	CCDS 1097.1	VCIP135	CCDS6192.1	ZKl	NM_001010879
TRIM55	CCDS6186.1	VCL	CCDS7340.1	ZMAT4	NM_024645
TRIM56	NM 030961	VDP	NM_003715	ZNF10	CCDS9283.1
TRIM58	CCDS 1636.1	VDR	CCDS8757.1	ZNF160	CCDS 12859.1
TRIO	CCDS3883.1	VGCNL1	CCDS9498.1	ZNF17	NM 006959
TRIOBP	NM_007032	VGLL2	CCDS5115.1	ZNF18	NM_144680
TRIP 12	NM_004238	VIPR2	CCDS5950.1	ZNF183L1	CCDS9486.1
TRIP6	CCDS5708.1	VMD2	NM 004183	ZNF189	CCDS6754.1
TRMT5	NM 020810	VN2R1P	ENST00000312652	ZNF25	CCDS7195.1
TRPC4AP	CCDS 13246.1	VPS 11	NM_021729	ZNF286	CCDS 11172.1
TRPC6	CCDS 8311.1	VPS13A	CCDS6655.1	ZNF294	NM_015565
TRPM2	CCDS13710.1	VPS24	NM 001005753	ZNF295	CCDS 13678.1
TRPM3	CCDS6634.1	VPS41	CCDS5457.1	ZNF30	NM_194325
TRPM4	ΝΜ 017636	VPS45A	CCDS944.1	ZNF31	NM_145238
TRPM5	NM_014555	VSIG2	CCDS 8452.1	ZNF313	ΝΜ 018683
TRPM6	CCDS6647.1	VWF	CCDS8539.1	ZNF318	CCDS4895.1
TRPM7	NM_017672	WBSCR17	CCDS5540.1	ZNF333	CCDS 12316.1
TRPV5	CCDS5875.1	WBSCR27	CCDS5561.1	ZNF339	CCDS13132.1
TRRAP	CCDS5659.1	WDFY3	CCDS3609.1	ZNF343	CCDS 13028.1
TSAP6	CCDS2125.1	WDR21	CCDS9809.1	ZNF358	ΝΜ 018083
TSC2	CCDS 10458.1	WDR22	NM 003861	ZNF366	CCDS4015.1
TSCOT	CCDS6786.1	WDR24	CCDS 10420.1	ZNF406	NM_001029939
TSGA10	CCDS2037.1	WDR27	NM_182552	ZNF440L	NM 001012753
TTC12	CCDS 8360.1	WDR32	CCDS6613.1	ZNF473	NM_015428
TTC18	CCDS7324.1	WDR34	CCDS6906.1	ZNF487	ENST00000315429
TTC6	ΝΜ 001007795	WDR42B	ENST00000329763	ZNF496	CCDS1631.1
TTLL2	CCDS5301.1	WDR52	CCDS2972.1	ZNF497	CCDS 12977.1
TTLL5	NM_015072	WDR6	CCDS2782.1	ZNF507	NM_014910
ΊΤΝ	NM_133378	WDR70	NM_018034	ZNF545	CCDS12493.1
ΊΤΝ	NM_133432	WDTC1	CCDS296.1	ZNF547	NM_173631
TUBGCP3	CCDS9525.1	WEE1	CCDS7800.1	ZNF558	CCDS 12208.1
TUBGCP6	CCDS 14087.1	WFS1	CCDS3386.1	ZNF585A	CCDS 12499.1
TULP1	CCDS4807.1	WNK1	CCDS 8506.1	ZNF628	NM_033113
TXNDC3	CCDS5452.1	WNK2	CCDS6704.1	ZNF67	ENST00000323012
TYR	CCDS 8284.1	WNT9A	NM_003395	ZNF79	CCDS6871.1
UBAP2L	CCDS 1063.1	XAB2	NM 020196	ZP2	CCDS 10596.1
UBE2G2	CCDS 13714.1	XDH	CCDS 1775.1	ZSCAN2	CCDS 10329.1
UCHL1	CCDS3462.1	XPO1	NM 003400	ZSWIM4	NM_023072
UGCGL2	CCDS9480.1	XPO7	NM_015024	ZW10	CCDS8363.1
UGDH	CCDS3455.1	XR_016172.1	ENST00000355015
UGT1A6	CCDS2510.1	XR 017335.1	ENST00000314295	Note: Gene symbols are standard
ULK1	CCDS9274.1	YN004 HUMAN	ENST00000281581	symbols assigned by Entrz Gene
UNQ2446	CCDS 10850.1	YTHDC2	CCDS4113.1	(http://www.ncbi.nlm.nih.gov/sites/ent
UNQ3030	CCDS3319.1	YWHAH	CCDS13901.1	rez?db=gene). Accession IDs

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Gene Symbol

7h3

AARS \BCAI

ABCA12

ABCA7

ABCB5

ABCD2 \B1I\I2

ACACB

ACT)

ACT

ACOT9

ACTE7B

ADA

AD AMI 1

ADAM12

ADAM19

ADAM21

AD AMTS 10

ADAMTS15

ADAMTS16

ADAMTS18

ADAMTS2

ADAMTS20

ADAMTS20

ADAMTS5

ADAMTSL3

ADCY2

ADCY4

ADD2

ADPRHL2

AFF3

AHNAK

AHNAK

AHR

AICDA

AIM2

AK3

AKAP12

ALDH18A1

ALDH1A3

ALDH3A1

ALDH3B1

ALDH8A1

AEG8

ALMS1

ALOX5

AMIGO3

Accession

ID

CCDS12324.1

NM 001605

CCDS6762.1

NM 015657

CCDS12055.1

CCDS5371.1

CCDS8734.1

NM 032432

NMOO1O93

CCDS 10842.1

CCDS11637.1

NM 001033583

CCDS6771.1

CCDS13335.1

CCDS11486.1

CCDS7653.1

CCDS4338.1

CCDS9804.1

CCDS 12206.1

CCDS8488.1

NM 139056

CCDS 10926.1

CCDS4444.1

NM 175851

NM 025003

CCDS13579.1

CCDS10326.1

CCDS3 872.1

CCDS9627.1

CCDS 1906.1

CCDS402.1

NM 001025108

NM_024060

NM 001620

CCDS5366.1

NM 020661

CCDS1181.1

CCDS629.1

CCDS5229.1

CCDS7443.1

CCDS10389.1

CCDS11212.1

NM 000694

CCDS5171.1

CCDS8258.1

NM015120

CCDS7212.1

NM_198722

Gene Symbol

ANAPC4

ANK3

ANKAR

ANKRD27

ANKRD6

ANKRD9

ANXA13

AOX1

AP3B2

APC2

APG4A

APOB

APRIN

APXL2

AQP8

ARFGAP1

ARHGAP10

ARHGAP21

ARHGAP28

ARHGEF11

ARHGEF7

ARHGEF9

ARID 1A

ARMC7

ARMCX1

ARNT2

ARRDC2

ARSA

ARSI

ARTS-1

ASB2

ASXL2

ATF2

ATN1

ATP10A

ATP10B

ATP10D

ATP11B

ATP1A3

ATP1B2

ATP2A1

ATP2B3

ATP6V0A4

AZU1

B3GAFT1

B3GNTF1

B4GAFT7

BACH2

BAI1

BAI3

BAIAP2F2

BAIAP3

BC37295_3

Accession

ID

CCDS3434.1

CCDS7258.1

ENSTOOOOO313581

NM 032139

NM_014942

CCDS9973.1

NM 001003954

NM_001159

NM 004644

CCDS12068.1

CCDS14538.1

CCDS 1703.1

NM 015032

CCDS4161.1

CCDS 10626.1

CCDS13515.1

NM_024605

CCDS7144.1

NM 001010000

CCDS 1162.1

CCDS9521.1

NMO15185

CCDS285.1

CCDS11714.1

CCDS 14487.1

NM_014862

CCDS 12370.1

CCDS 14100.1

NM_001012301

CCDS4085.1

CCDS9915.1

NM_018263

CCDS2262.1

NM 001940

NM_024490

ENST00000327245

CCDS3476.1

NM_014616

CCDS 12594.1

NM 001678

CCDS10643.1

CCDS 14722.1

CCDS5849.1

CCDS 12044.1

CCDS2227.1

NM 001009905

CCDS4429.1

CCDS5026.1

NM 001702

CCDS4968.1

NM 025045

CCDS 10434.1

NM_001005850

Gene Symbol

BCAN

BCHE

BCE2A1

Beta4GalNAc-T4

BMPR2

BOC

BPIF3

BRCA2

BSN

BTBD7

C10orfll3

C10orf31

C10orf93

C10orf99

Cllorfl6

C13orf22

C13orf25

C14orfl21

C14orfl24

C15orfl6

C15orf41

C17orf27

C17orf38

C19orf20

C19orf22

C19orf28

C19orf35

C19orf6

Clorfll3

Clorfl29

Clorfl4

Clorf25

Clorf45

C1QE2

C1RL

C20orfl34

C20orfl61

C20orf26

C20orf42

C20orf77

C21orf29

C21orf63

C2orfl0

C2orf29

C3

C3orfl5

C3orfl8

C4orf9

C6orfl03

C6orf213

C6orf54

C6orf60

C7orf27

Accession

ID

CCDS 1149.1

CCDS3198.1

CCDS 10312.1

CCDS7694.1

NM_001204

CCDS2971.1

CCDS13211.1

CCDS9344.1

CCDS2800.1

NM 001002860

NM_001010896

NM 001012713

CCDS7672.1

CCDS7371.1

CCDS7794.1

CCDS9336.1

CCDS9467.1

NM 138360

NM 020195

CCDS 10026.1

NM 032499

NM 020914

NM_001010855

NMO33513

CCDS12048.1

NM_174983

CCDS12087.1

CCDS12052.1

NM_024676

NM 025063

NMO3O933

CCDS 1366.1

NM 001025231

NM 182528

CCDS8573.1

NM 001024675

CCDS13377.1

NM_O15585

CCDS13098.1

CCDS13301.1

CCDS13712.1

CCDS13614.1

CCDS2291.1

CCDS2050.1

NM 000064

CCDS2994.1

CCDS2829.1

NMOO37O3

ENST00000326916

NM_001010852

CCDS5304.1

NM 024581

CCDS5334.1

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Gene Symbol C9orfl38	Accession ID CCDS6487.1	Gene Symbol CFHR4	Accession ID NM 006684	Gene Symbol CTAG2	Accession ID CCDS 14759.1
C9orf39	NM_017738	CGI-09	CCDS 13093.1	CTTNNA2	NM_004389
C9orf45	CCDS6850.1	CGN	CCDS999.1	CTNNA3	CCDS7269.1
?9orl9l	CCDS6808.1	CHD1	NM 001270	CTNND2	CCDS3881.1
C9orf98	CCDS6954.1	CHD5	CCDS57.1	CUBN	CCDS7113.1
CABLES2	NM031215	CHD7	NM 017780	CUL4B	NM 003588
CACNA1A	NM 000068	CHI3L1	CCDS1435.1	CUTL1	CCDS5720.1
CACNA1E	NM_000721	CHMP1B	NM_020412	CX40.1	CCDS7191.1
CACNA2D1	CCDS5598.1	CHPPR	CCDS6182.1	CXorf9	CCDS14614.1
CACNG5	CCDS11666.1	CHST1	CCDS7913.1	CYFIP1	CCDS 10009.1
?AI)	CCDS 1742.1	CHURC1	NM_145165	CYFIP2	NM_014376
CALB1	CCDS6251.1	CIAS1	CCDS1632.1	CYP1A1	CCDS 10268.1
CALCR	CCDS5631.1	CILP	CCDS 10203.1	DACH2	CCDS 14455.1
CAMSAP1	NM_015447	CKLFSF4	CCDS10817.1	DAXX	CCDS4776.1
CAMTA1	NM015215	CLEC4M	CCDS12187.1	DBT	CCDS767.1
CAND2	ENST00000295989	CLIPR-59	CCDS12486.1	DCC1	CCDS6330.1
CAPN12	CCDS12519.1	CLK1	CCDS2331.1	DCHS1	CCDS7771.1
CARD9	CCDS6997.1	CLSTN2	CCDS3112.1	DCHS2	CCDS3785.1
CASKIN2	CCDS11723.1	CLUAP1	NM 015041	DCT	CCDS9470.1
CASP10	CCDS2338.1	CMAS	CCDS8696.1	DDX51	NM_175066
CAT	CCDS7891.1	CMYA1	CCDS2683.1	DDX58	CCDS6526.1
CBFA2T2	CCDS 13221.1	CMYA3	NM 152381	DEPDC2	CCDS6201.1
CBLN4	CCDS13448.1	CMYA5	NM_153610	DEPDC5	NM_014662
CCDC11	CCDS11940.1	CNGB1	NM 001297	DET1	NM 017996
CCDC18	NM 206886	CNGB3	CCDS6244.1	DFNB31	CCDS6806.1
CCKAR	CCDS3438.1	CNTN4	CCDS2558.1	DGKA	CCDS8896.1
CCL2	CCDS11277.1	CNTN5	NM 014361	DGKD	CCDS2504.1
CCNB3	CCDS14331.1	CNTN6	CCDS2557.1	DGKK	NM 001013742
CCNYL3	ENST00000332505	CNTNAP2	CCDS5889.1	DGKZ	CCDS7918.1
CCR1	CCDS2737.1	CNTNAP4	CCDS 10924.1	DHCR24	CCDS600.1
CCT6A	CCDS5523.1	COBLL1	CCDS2223.1	DHX33	CCDS11072.1
7(1615	NM_006584	COCH	CCDS9640.1	DHX8	CCDS 11464.1
2D 163	CCDS8578.1	COH1	CCDS6280.1	DICER 1	CCDS9931.1
CD1A	CCDS1174.1	COL11A1	CCDS778.1	DIP2B	NM 173602
CD200R1	CCDS2969.1	COL14A1	NM_021110	DKFZp313G1735	CCDS4073.1
CD44	CCDS7897.1	COL17A1	CCDS7554.1	DKFZP434B0335	NMO15395
CD6	CCDS7999.1	COL22A1	CCDS6376.1	DKFZP434G1415	CCDS8743.1
CD79A	CCDS12589.1	COL4A1	CCDS9511.1	DKFZP434L1717	CCDS3805.1
CD86	CCDS3009.1	COL4A4	NM 000092	DKFZp434O0527	CCDS2430.1
CDC42BPA	CCDS1558.1	COL5A1	CCDS6982.1	DKFZP564J0863	NM 015459
CDH1	CCDS10869.1	COL6A3	NM_004369	DKFZp566O084	CCDS11215.1
CDH10	CCDS3 892.1	COEEC12	NM 130386	DKFZP586P0123	NMO15531
CDH20	CCDS11977.1	CORO2A	CCDS6735.1	DKFZp761A052	CCDS14313.1
CDH7	CCDS11993.1	CPAMD8	NM_015692	DLC1	CCDS5989.1
CDKN2A	CCDS6510.1	CPLX2	ENST00000274615	DLEC1	ENST00000337335
CDSN	NM 001264	CPN1	CCDS7486.1	DLG2	NM 001364
CEBPZ	CCDS1787.1	CPT1C	CCDS 12779.1	DLG3	CCDS14403.1
CEECAM1	CCDS6901.1	CPZ	CCDS3404.1	DLGAP1	CCDS11836.1
CEL	NM 001807	CREBBP	CCDS 10509.1	DMD	CCDS14228.1
CELSR1	CCDS14076.1	CSF2RB	CCDS 13936.1	DMP1	CCDS3623.1
CENTD1	CCDS3441.1	CSMD1	NM 033225	DNA2L	ENST00000358410
Cepl92	NM 032142	CSMD2	CCDS380.1	DNAH11	NM 003777
CEP290	NM_025114	CSS3	NM_175856	DNAH5	CCDS3882.1

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Gene Symbol DNAH8	Accession ID CCDS4838.1	Gene Symbol EPPKl	Accession ID NMO313O8	Gene Symbol FLJ20457	Accession ID CCDS6774.1
DNAH9	CCDS11160.1	EPS8L2	NM_022772	FLJ20580	CCDS576.1
DNAPTP6	NMO15535	ERCC2	NM 000400	FLJ21628	CCDS4440.1
DNHD2	NM 178504	ERCC4	NM 005236	FLJ21816	NM 024675
DNM1L	CCDS8728.1	ERCC6	CCDS7230.1	FLJ21986	NM_024913
DOCK2	CCDS4371.1	EST1B	CCDS1137.1	FLJ23420	CCDS12189.1
DOT1L	NM 032482	ETS2	CCDS13659.1	FLJ23577	ENST00000303168
DP58	NM_001004441	ETV6	CCDS8643.1	FLJ23588	CCDS 14049.1
DPP6	NM 130797	EVI1	CCDS3205.1	FLJ25006	CCDS11237.1
DRD2	CCDS8361.1	EVPL	CCDS11737.1	FLJ25530	CCDS8456.1
DRD3	CCDS2978.1	EXOC2	NM_018303	FLJ26175	NM_001001668
DUOX2	CCDS10117.1	EXOSC8	NM181503	FLJ31295	CCDS8763.1
DUSP15	CCDS13193.1	F10	CCDS9530.1	FLJ32110	CCDS5613.1
DUSP19	CCDS2289.1	F13A1	CCDS4496.1	FLJ32112	CCDS587.1
DYSF	CCDS1918.1	F8	NM 000132	FLJ32416	CCDS 12086.1
EBF	CCDS4343.1	FAD158	CCDS725.1	FLJ32685	CCDS2645.1
EBF3	NM_001005463	FADD	CCDS8196.1	FLJ34969	NM_152678
EDG8	CCDS 12240.1	FADS1	CCDS8013.1	FLJ35220	NM 173627
EFEMP1	CCDS1857.1	FADS2	CCDS8012.1	FLJ35843	CCDS9151.1
EHMT1	CCDS7050.1	FAM132B	ENST00000344233	FLJ36180	CCDS3851.1
EIF2AK2	CCDS1786.1	FAM47B	ENST00000329357	FLJ36748	NM 152406
EIF5	CCDS9980.1	FAM50B	CCDS4487.1	FLJ37396	CCDS5072.1
EIF5B	NM_015904	FAM53B	CCDS7641.1	FLJ38020	NM_001039775
ELA2	CCDS12045.1	FAM54B	NM 019557	FLJ38377	CCDS2164.1
ELAVL4	CCDS553.1	FAM55C	CCDS2945.1	FLJ39155	CCDS3924.1
ELN	CCDS5562.1	FAT	NM_005245	FLJ39501	CCDS12331.1
EME2	NM 001010865	FAT3	ENST00000298047	FLJ39502	CCDS2281.1
EMILIN1	CCDS1733.1	FAT4	CCDS3732.1	FLJ40235	CCDS12827.1
EML1	NM_004434	FBN2	NM_001999	FLJ41046	NM_207479
ENC1	CCDS4021.1	FBN3	CCDS12196.1	FLJ41993	NM 001001694
ENST00000294635	ENST00000294635	FBXO15	CCDS 12002.1	FLJ45231	NM 001039778
ENST00000298876	ENST00000298876	FBXO3	CCDS7887.1	FLJ45909	CCDS12522.1
ENST00000309390	ENST00000309390	FBXO41	ENST00000295133	FLJ46072	CCDS6410.1
ENST00000322493	ENST00000322493	FBXO9	NM 033481	FLJ46365	CCDS6144.1
ENST00000324303	ENST00000324303	FBXW7	CCDS3777.1	FLJ46481	CCDS3384.1
ENST00000326382	ENST00000326382	FBXW8	CCDS9182.1	FLJ46536	NM 198483
ENST00000326952	ENST00000326952	FGD2	CCDS4829.1	FLJ90805	CCDS 12603.1
ENST00000332477	ENST00000332477	FGD5	NM_152536	FMN2	NM_020066
ENST00000333971	ENST00000333971	FKRP	CCDS12691.1	EMNL1	CCDS11497.1
ENST00000334548	ENST00000334548	FKSG44	CCDS8102.1	FMNL3	NM 175736
ENST00000336168	ENST00000336168	FLJ10324	NM_018059	FMR1	CCDS14682.1
ENST00000340260	ENST00000340260	FLJ10407	CCDS583.1	EMR2	CCDS14684.1
ENST00000356555	ENST00000356555	FLJ10521	CCDS182.1	FN1	CCDS2399.1
ENTH	NM_014666	FLJ10647	CCDS406.1	FOXJ1	NM_001454
EP300	CCDS14010.1	FLJ12886	NMO191O8	FOXP2	CCDS5760.1
EPB41L1	CCDS 13271.1	FLJ14011	CCDS 12944.1	FREM1	NM 144966
EPC2	NM_015630	FLJ14299	CCDS6094.1	FREM2	NM_207361
EPHA3	CCDS2922.1	FLJ 14490	CCDS446.1	FRMPD4	NM 014728
EPHA7	CCDS5031.1	FLJ 14640	NM 032816	FSTL5	CCDS3 802.1
EPHB1	NM_004441	FLJ20032	CCDS3666.1	FTCD	CCDS13731.1
EPHB2	CCDS229.1	FLJ20035	NM 017631	FTHL17	CCDS14227.1
EPHB6	CCDS5873.1	FLJ20244	CCDS12293.1	GAB RAI	CCDS4357.1
EPM2A	CCDS5206.1	FLJ20245	CCDS7041.1	GABRR1	CCDS5019.1

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Gene Symbol 3ALNT13	Accession ID CCDS2199.1	Gene Symbol HELB	Accession ID CCDS8976.1	Gene Symbol KBTBDll
3ALNT4	NM_003774	HELZ	NM_014877	KCNA3
3ALNT8	CCDS8533.1	HIP1	NMOO5338	KCNA4
3AS7	CCDS11152.1	HIST1H3A	CCDS4570.1	KCNB1
3BP3	CCDS717.1	HIST1H4I	CCDS4620.1	KCNB2
3DF6	NM 001001557	HKR2	CCDS12975.1	KCNC2
3FAP	CCDS 11491.1	HMGCLL1	NM 019036	KCNC3
3FRA1	CCDS7593.1	HOXC10	CCDS8868.1	KCNJ3
3H2	CCDS11648.1	HOXC9	CCDS8869.1	KCNK10
3IMAP7	CCDS5903.1	HOXD4	CCDS2269.1	KCNMA1
3JA3	CCDS9289.1	HPCAL1	CCDS1671.1	KCNT1
3LB1L3	ENST00000299136	HPS5	CCDS7836.1	KCTD15
3LI1	CCDS8940.1	HRB2	CCDS9012.1	KEAP1
3LI3	CCDS5465.1	HRPT2	CCDS1382.1	KIAA0082
3LP1R	CCDS4839.1	HS3ST2	CCDS 10606.1	KIAA0317
3LTSCR1	NM015711	HS3ST5	NM_153612	KIAA0367
3NAT1	CCDS2812.1	HSGT1	CCDS7321.1	KIAA0372
3OLGA3	CCDS9281.1	HTR1A	NM 000524	KIAA0590
3PC2	CCDS5689.1	HYPC	CCDS8789.1	KIAA0774
3PR	CCDS 10051.1	IER5	CCDS1343.1	KIAA1024
3PR110	ENST00000326374	IL12RB1	NM 153701	KIAA1086
3PR133	CCDS9272.1	IL17RB	CCDS2874.1	KIAA1102
3PR151	NM_194251	IL17RC	CCDS2590.1	KIAA1109
3PR154	CCDS5443.1	IL18R1	CCDS2060.1	KIAA1219
3PR158	NM 020752	IL2RG	CCDS 14406.1	KIAA1543
3PR35	CCDS2541.1	ILK	CCDS7768.1	KIAA1704
3PR54	CCDS12049.1	IMP5	NM 175882	KIAA1751
3PR73L1	CCDS13089.1	INHBB	CCDS2132.1	KIAA1755
3PR82	CCDS14259.1	INO80	CCDS10071.1	KIAA1944
3PRC5C	CCDS11699.1	INPP5D	NM 001017915	KIAA1957
3PS2	CCDS11100.1	INTS2	NM 020748	KIAA1961
3PX6	NM_182701	IQGAP1	CCDS 10362.1	KIAA2013
3RCA	CCDS8563.1	IRGQ	NM 001007561	KIF21A
3RHL1	NM_198182	IRS4	CCDS 14544.1	KIF25
GRIA3	CCDS14604.1	IRX1	NM_024337	KIF3A
GRIK2	CCDS5048.1	ISYNA1	CCDS 12379.1	KIN
GRIN3A	CCDS6758.1	ITGA11	NM 001004439	KIRREL
GRIP2	ENST00000273083	ITGA3	CCDS11557.1	ΚΓΓ
GRM6	CCDS4442.1	ITGA4	NM 000885	KLF5
GRM8	CCDS5794.1	ITGA9	CCDS2669.1	KLHDC1
GSDML	CCDS11354.1	ITGAE	NM_002208	KLHDC4
GSR	NM 000637	ITGB4BP	CCDS 13249.1	KLP1
GTF3C1	NM 001520	ΓΠΗ2	NM 002216	KPNB1
GTF3C3	CCDS2316.1	ITLN1	CCDS1211.1	KRAS
GUCA2A	CCDS465.1	ITPR1	NM 002222	KRT13
GUCY1A2	CCDS8335.1	IXL	NM 017592	KRT9
H1T2	CCDS8762.1	JAG1	CCDS 13112.1	KRTAP11-1
HAPLN4	CCDS12398.1	JM11	CCDS 14316.1	L3MBTL4
HAS1	CCDS12838.1	JMJD3	ENST00000254846	LAMA1
HBXIP	CCDS824.1	JPH3	CCDS 10962.1	LAMA4
HCK	NM 002110	JPH4	CCDS9603.1	LAMA5
HECW1	CCDS5469.1	K6IRS2	CCDS8833.1	LAMC3
HECW2	NM_020760	KALI	CCDS14130.1	LARP

Accession

ID

NM 014867

CCDS828.1

NM 002233

CCDS13418.1

CCDS6209.1

CCDS9005.1

CCDS12793.1

CCDS2200.1

CCDS9880.1

CCDS7352.1

NM_020822

CCDS 12434.1

CCDS 12239.1

CCDS4835.1

ENST00000338772

NM 015225

CCDS4072.1

CCDS10439.1

NM 001033602

NM_015206

ENST00000262961

NM 014988

ENST00000264501

CCDS13305.1

ENST00000160298

CCDS9394.1

ENST00000270720

NM 001029864

CCDS9266.1

ENST00000332235

NM 133372

ENST00000329923

NM 017641

CCDS5305.1

NM_007054

CCDS7080.1

CCDS1172.1

CCDS3496.1

CCDS9448.1

CCDS9692.1

CCDS 10963.1

CCDS 12926.1

CCDS11513.1

CCDS8702.1

CCDS11396.1

NM 000226

CCDS13608.1

CCDS11839.1

NMOO5559

NM_002290

NM 005560

CCDS6938.1

CCDS4328.1

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Gene Symbol	Accession ID	Gene Symbol
LASS3	CCDS 103 84.1	LRRN3
LCT	CCDS2178.1	LRRTM4
LENG8	CCDS 12894.1	MAGEE1
LGI4	CCDS 12444.1	MAMDC1
LGR6	CCDS1424.1	MAN2A1
LIG3	CCDS11284.1	ΜΑΡΙΑ
LIMR	CCDS8780.1	MAP1B
LIPH	CCDS3272.1	MAP2
LMOD1	NM012134	MAP2K6
LMTK2	CCDS5654.1	MAP4K2
LMX1A	CCDS1247.1	MAP4K3
LOCI 13179	CCDS 12076.1	MAP4K4
LOCI 13386	NM_138781	MAPKBP1
LOC123872	CCDS 10943.1	MAPT
LOC126147	NM 145807	MARLIN1
LOC128153	CCDS1519.1	MARS
LOC130951	NM_138804	MASP2
LOC131873	ENST00000358511	MASS1
LOC163131	NM 001005851	MAST2
LOC167127	CCDS3914.1	MAT2B
LOC222967	ENST00000297186	MBD3
LOC283219	NM 001029859	MCM7
LOC283398	ENST00000342823	MCTP2
LOC284434	NM 001007525	MEGF11
LOC339768	CCDS2525.1	ΜΕΡΙΑ
LOC340578	NM_001013628	METTL3
LOC342979	ENST00000340790	MGC10731
LOC343521	NM 001013632	MGC13125
LOC387720	NM_001013633	MGC 15523
LOC388135	NM 001039614	MGC15875
LOC392617	ENST00000333066	MGC20806
LOC399706	NM_001010910	MGC2494
LOC441136	NM 001013719	MGC26598
LOC441476	NM 001004353	MGC26988
LOC441722	ENST00000311061	MGC29649
LOC51334	CCDS4127.1	MGC33407
LOC63920	NM 022090	MGC34713
LOC89944	NM_138342	MGC35138
LPAL2	ENST00000342479	MGC35555
LPHN3	NM 015236	MGC39581
LPL	CCDS6012.1	MGC4266
LRFN5	CCDS9678.1	MGC50721
LRP1	CCDS8932.1	MGC5297
LRP1B	CCDS2182.1	MIDI
LRP2	CCDS2232.1	MIZF
LRP3	CCDS12430.1	MKL2
LRP5	CCDS8181.1	MLC1
LRRC16	NM 017640	MLL
LRRC18	NM 001006939	MLL2
LRRC3B	CCDS2644.1	MLL3
LRRC4	CCDS5799.1	MLL5
LRRC48	NM 031294	MMP9
LRRK2	NM_198578	MOBKL2C

Accession ID CCDS5754.1	Gene Symbol MORC	Accession ID CCDS2955.1
NM_024993	MORC2	NM_014941
CCDS14433.1	MOXD1	CCDS5152.1
NM 182830	MPHOSPH1	CCDS7407.1
NM_002372	MPL	CCDS483.1
NM 002373	MPN2	CCDS 1563.1
CCDS4012.1	MPO	CCDS 11604.1
CCDS2384.1	MPZ	CCDS 1229.1
CCDS11686.1	MRGPRD	ENST00000309106
CCDS8082.1	MRGX1	CCDS7846.1
CCDS 1803.1	MRPL38	CCDS11733.1
ENST00000302217	MRPS7	CCDS11718.1
NM 014994	MSLN	NM 013404
CCDS11499.1	MTF1	NM_005955
CCDS3385.1	MTMR12	NM 019061
CCDS8942.1	MTMR2	CCDS8305.1
CCDS 123.1	MTO1	CCDS4979.1
NM 032119	MTR	CCDS1614.1
NM015112	MUC1	CCDS1098.1
CCDS4365.1	MUC15	CCDS7859.1
CCDS 12072.1	MUC16	NM 024690
CCDS5683.1	MUC2	NM 002457
NM_018349	MUF1	CCDS533.1
CCDS10213.1	MUM1L1	NM_152423
CCDS4918.1	MYBL1	ENST00000331406
NM_019852	MYBPHL	NM_001010985
CCDS171.1	MYCBPAP	NM 032133
CCDS8374.1	MYH2	CCDS11156.1
CCDS11780.1	MYH3	CCDS11157.1
CCDS4434.1	MYH6	CCDS9600.1
CCDS11797.1	MYH9	CCDS13927.1
CCDS10423.1	MYLIP	CCDS4536.1
CCDS9036.1	MYO10	NM 012334
CCDS4335.1	MYO15A	NM 016239
CCDS8033.1	MYO1G	NM_033054
CCDS 12207.1	MYO3A	CCDS7148.1
CCDS4070.1	MYO6	NM 004999
CCDS7701.1	MYO7B	ENST00000272666
CCDS6307.1	MYO9A	CCDS10239.1
CCDS12149.1	MYOM1	NM 003803
CCDS8522.1	MYST3	CCDS6124.1
CCDS 10602.1	NAALAD2	CCDS8288.1
CCDS3873.1	NAALADL2	NM 207015
CCDS14138.1	NALP10	CCDS7784.1
CCDS8414.1	NALP13	NM 176810
NM 014048	NALP14	CCDS7776.1
CCDS 14083.1	NALP4	CCDS12936.1
NM 005933	NAV2	CCDS7850.1
NM 003482	NAV3	NM 014903
CCDS5931.1	NCDN	CCDS392.1
NM 182931	NCK1	CCDS3092.1
CCDS 13390.1	NCL	NMOO5381
CCDS539.1	NCOA2	NM_006540

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Gene Symbol NEB	Accession ID NM 004543	Gene Symbol OR2W3	Accession ID NM 001001957	Gene Symbol PCDHB2	Accession ID CCDS4244.1
NEK8	NM_178170	OR4A16	NM_001005274	PCDHB3	CCDS4245.1
ΝΕΟΙ	CCDS10247.1	OR4B1	NM 001005470	PCDHGA1	NMO31993
NFATC3	CCDS 10860.1	OR4E2	NM 001001912	PCDHGA11	NM 032091
NFIA	CCDS615.1	OR4L1	NM_001004717	PCDHGA8	NM_014004
NID	CCDS1608.1	OR4X1	NM 001004726	PCDHGC4	CCDS4260.1
NID2	CCDS9706.1	OR51B4	CCDS7757.1	PONT	NM 006031
NIF3F1BP1	CCDS2900.1	OR51E1	NM_152430	PCNXL2	ENST00000344698
NIPSNAP3B	CCDS6761.1	OR51F2	NM 001004753	PCSK2	CCDS13125.1
NKX2-2	CCDS13145.1	OR52I2	NM 001005170	PCSK6	NM 138321
NFGN1	CCDS3222.1	OR52L1	ENST00000332249	PDE6A	CCDS4299.1
NMUR1	CCDS2486.1	OR5C1	NM 001001923	PDZRN3	NM 015009
NOD3	NM 178844	OR5D13	NM 001001967	PDZRN4	CCDS8739.1
NOL5A	CCDS13030.1	OR5D3P	ENST00000333984	PEG3	CCDS 12948.1
NOPE	CCDS 10206.1	OR5F1	NM 003697	PER3	CCDS89.1
NOR1	CCDS409.1	OR5J2	NM 001005492	PFAS	CCDS11136.1
NOS1	NM_000620	OR5T1	NM_001004745	PGM5	CCDS6622.1
NOX5	NM 024505	OR6A2	CCDS7772.1	PGR	CCDS8310.1
NP 001035826.1	ENST00000331090	OR6K2	NM 001005279	PHACTR3	CCDS13480.1
NP_001074311.1	ENST00000326096	OR8D2	NM_001002918	PHB2	NM_007273
NPD014	CCDS260.1	OR8H1	NM 001005199	PIAS4	CCDS12118.1
NPHP4	NM015102	OR8K1	NM 001002907	PICK	CCDS674.1
NPY1R	NM_000909	OR8K5	NM_001004058	PICT	CCDS13353.1
NRG2	CCDS4217.1	OR9I1	NM 001005211	PIK3CG	CCDS5739.1
NRXN2	CCDS8077.1	OR9K2	NM 001005243	PIK3R2	CCDS12371.1
NRXN3	CCDS9870.1	ORC5L	CCDS5734.1	PIP5K3	CCDS2382.1
NSE1	CCDS 1684.1	OSBPL6	CCDS2277.1	PTTRM1	NM 014889
NTF3	CCDS8538.1	OSCAR	CCDS12873.1	PKD1F2	NM_182740
NTRK3	CCDS 10340.1	OSMR	CCDS3928.1	PKHD1F1	NM_177531
NUDT5	CCDS7089.1	OSTN	CCDS3299.1	PKIA	CCDS6222.1
ENST00000318605	ENST00000318605	OTOF	CCDS 1724.1	PKP2	CCDS8731.1
NUP210	NM_024923	OTP	CCDS4039.1	PLCB2	NM_004573
NURIT	CCDS9399.1	OTX1	CCDS1873.1	PLCB3	CCDS8064.1
NXN	CCDS10998.1	OVCA2	NM 001383	PLCB4	CCDS13104.1
NXPH3	CCDS11550.1	OVCH1	NM_183378	PLEC1	NM_201380
OBSCN	CCDS1570.1	Pll	CCDS8754.1	PLEC1	NM 201378
OBSL1	ENST00000265318	PABPC5	CCDS 14460.1	PFEK2	CCDS9782.1
OCA2	CCDS 10020.1	PACS2	NM_015197	PLEKHA6	CCDS1444.1
ODZ4	ENST00000278550	PADI2	CCDS177.1	PLEKHG2	NM 022835
OGDHL	CCDS7234.1	PAEMD	CCDS758.1	PLK5HUMAN	ENST00000334770
OGFOD2	NM_024623	PAPPA	CCDS6813.1	PLXNA1	NM_032242
OGT	CCDS14414.1	PARP10	NM 032789	PLXNB1	CCDS2765.1
OR10A3	ENST00000360759	PARP14	NM 017554	PMP22CD	NM 001013743
OR10K2	NM_001004476	PARP2	NM_005484	PNPLA1	NM_001039725
OR10P1	NM 206899	PARP9	CCDS3014.1	PODN	CCDS573.1
OR10R2	NM 001004472	PAX6	NM 000280	PODXF	NM001018111
OR10Z1	NM_001004478	PB1	CCDS2859.1	POFR2A	NM_OOO937
OR11L1	NM 001001959	PCDH15	CCDS7248.1	POFRMT	CCDS12036.1
OR13C3	NM 001001961	PCDH17	NM 014459	PON1	CCDS5638.1
OR13C5	NM_001004482	PCDH18	NM_019035	PPA2	CCDS3667.1
OR1J2	NM 054107	PCDH9	CCDS9443.1	PPFIA2	NM 003625
OR2AJ1	ENST00000318244	PCDHA13	NM 031864	PPP1CA	CCDS8160.1
OR2T1	NM_030904	PCDHB16	CCDS4251.1	PPP1R15B	CCDS1445.1

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Gene Symbol PPP1R3A	Accession ID CCDS5759.1	Gene Symbol Q96M18HUMAN	Accession ID ENST00000335239	Gene Symbol RODH	Accession ID CCDS8925.1
PPP2R1A	CCDS12849.1	Q96MJ2_HUMAN	ENST00000327832	RP1	CCDS6160.1
PPP2R3A	CCDS3087.1	Q96QE0_HUMAN	ENST00000301647	RPGRIP1	NM 020366
PPP2R4	CCDS6920.1	Q96RX8HUMAN	ENST00000301719	RREB1	NM 001003699
PPP5C	CCDS 12684.1	Q96S27_HUMAN	ENST00000301682	RTL1	ENST00000331067
PRDM10	CCDS8484.1	Q9H557 HUMAN	ENST00000237253	RTTN	NM 173630
PRDM5	CCDS3716.1	Q9H5F0HUMAN	ENST00000360484	RUNX1T1	CCDS6256.1
PRDM9	NM_020227	Q9H8A7_HUMAN	ENST00000053084	RYR1	NM_000540
PRELP	CCDS1438.1	Q9HA39_HUMAN	ENST00000329980	RYR2	NM 001035
PREX1	CCDS 13410.1	Q9HCM3HUMAN	ENST00000242365	SACS	CCDS9300.1
PRG-3	CCDS6751.1	Q9NSI0_HUMAN	ENST00000328881	SARS2	NM_017827
PRKACG	CCDS6625.1	Q9NT86HUMAN	ENST00000314272	SART3	CCDS9117.1
PRKCG	CCDS12867.1	Q9P169_HUMAN	ENST00000342338	SBLF	CCDS 1840.1
PRKD1	CCDS9637.1	Q9P193_HUMAN	ENST00000359406	SCAP2	CCDS5400.1
ProSAPiPl	CCDS13049.1	Q9P1M5HUMAN	ENST00000303007	SCFD2	NM 152540
PRR12	ENST00000246798	Q9Y6V0-3	ENSTOOOOO333891	SCGN	CCDS4561.1
PRSS23	CCDS8278.1	QRICH2	NM_032134	SCN11A	NM_014139
PSMD3	CCDS11356.1	RAB6B	CCDS3082.1	SCN2A2	NM 021007
PSME4	NM014614	RAD9B	CCDS9148.1	SCN4A	NM 000334
PTCHD2	ENST00000294484	RAG1	CCDS7902.1	SCN5A	NM_000335
PTCHD3	NM 001034842	RAG2	CCDS7903.1	SCN5A	NM 198056
PTF1A	CCDS7143.1	RaLP	CCDS10130.1	SCN7A	NM 002976
PTGER3	CCDS652.1	RANBP2	CCDS2079.1	SCNM1	CCDS987.1
PTN	CCDS5844.1	RARB	CCDS2642.1	SCNN1B	CCDS10609.1
PTPN12	CCDS5592.1	RARRES2	CCDS5902.1	SCNN1G	CCDS10608.1
PTPRK	CCDS5137.1	RASEF	ENST00000330861	SCRIB	CCDS6411.1
PTPRZ1	NM 002851	RASGRP3	NM 170672	SDPR	CCDS2313.1
PUM1	CCDS338.1	RASGRP4	NM 170603	SDS	CCDS9169.1
PWP2H	NM_005049	RASIP1	CCDS 12731.1	SEC14L3	CCDS13877.1
PXDN	ENST00000252804	RASSF6	CCDS3558.1	SEMA4D	CCDS6685.1
PXDNL	NM 144651	RBAF600	CCDS189.1	SEMA5B	CCDS3019.1
PYHIN1	CCDS1178.1	RBBP6	CCDS10621.1	SENP1	NM_014554
Q08AG5HUMAN	ENST00000334213	RBM27	ENST00000265271	SESN2	CCDS321.1
Q5JX50HUMAN	ENST00000325076	RC74	NM 018250	SEZ6L	CCDS13833.1
Q5SYT8_HUMAN	ENST00000279434	RCHY1	CCDS3567.1	SF3A1	CCDS13875.1
Q6ZMX6HUMAN	ENST00000269197	RDH8	CCDS12223.1	SF3B1	NM 012433
Q6ZT40HUMAN	ENST00000296564	RELN	NM 005045	SFRS12	CCDS3991.1
Q7Z2Q7_HUMAN	ENST00000334994	RENBP	CCDS 14738.1	SFRS16	CCDS12652.1
Q7Z7L8HUMAN	ENST00000339446	REPIN1	NM 013400	SGEF	NMO15595
Q8N2V9_HUMAN	ENST00000324414	RFX1	CCDS12301.1	SH2D1B	NM 053282
Q8N5S4_HUMAN	ENST00000326474	RFX3	CCDS6449.1	SH3GL3	CCDS10325.1
Q8N6V7HUMAN	ENST00000324928	RFXDC1	CCDS5113.1	SH3TC1	CCDS3399.1
Q8N800 HUMAN	ENST00000322516	RGS11	CCDS10403.1	SHANK2	CCDS8198.1
Q8N9F6_HUMAN	ENST00000317122	RGS17	CCDS5244.1	SHKBP1	CCDS12560.1
Q8N9G5HUMAN	ENST00000313957	RHBDF1	NM 022450	SI	CCDS3196.1
Q8N9S5HUMAN	ENST00000329388	RHOT2	CCDS10417.1	SIDT1	CCDS2974.1
Q8N9V7_HUMAN	ENST00000309765	RIC3	CCDS7788.1	SIGLEC11	CCDS 12790.1
Q8N9Z1HUMAN	ENST00000326413	RIMBP2	NM 015347	SIPA1L2	NM 020808
Q8NCK2HUMAN	ENST00000325720	RIMS1	NM 014989	SIX2	CCDS 1822.1
Q8NGP7_HUMAN	ENST00000341231	RIMS2	NM_014677	SKD3	CCDS8215.1
Q8NH06HUMAN	ENST00000324144	RLF	CCDS448.1	SLC14A1	CCDS11925.1
Q8NH08HUMAN	ENST00000327198	RNF175	NM 173662	SLC17A1	CCDS4565.1
Q96GK3_HUMAN	ENST00000315264	RNUT1	CCDS10281.1	SLC17A7	CCDS 12764.1

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Gene Symbol SLC1A6	Accession ID CCDS12321.1	Gene Symbol STAC	Accession ID CCDS2662.1	Gene Symbol TM9SF4	Accession ID CCDS13196.1
SLC22A15	NM_018420	STAC2	CCDS11335.1	TMCC2	NM_014858
SLC22A7	CCDS4893.1	STAMBP	CCDS1929.1	TMEEF2	CCDS2314.1
SLC25A26	CCDS2905.1	STARD13	CCDS9348.1	TMEM132B	NM 052907
SLC28A3	CCDS6670.1	STARD8	CCDS14390.1	TMEM16A	NM_018043
3LC2A1	CCDS477.1	STAT4	CCDS2310.1	TMEM16C	NM031418
SLC2A3	CCDS8586.1	STIM1	CCDS7749.1	TMEM16G	NM 001001891
SLC2A5	CCDS99.1	STK10	NM_005990	TMEM63B	NM_018426
3LC33A1	CCDS3173.1	STK23	NM 014370	TMEM8	CCDS 10407.1
SLC39A10	NM 020342	STK33	CCDS7789.1	TMEPAI	CCDS 13462.1
SLC39A6	NM_012319	STMN4	CCDS6055.1	TMPO	CCDS9064.1
SLC45A1	ENST00000289877	STN2	CCDS9875.1	TMPRSS13	NM 032046
SLC4A10	NM 022058	SULF1	CCDS6204.1	TNF	CCDS4702.1
SLC4A8	CCDS8814.1	SULF2	CCDS13408.1	TNFRSF8	CCDS144.1
3LC4A9	NM 031467	SV2A	CCDS940.1	TNK1	NMOO3985
SLC6A15	CCDS9026.1	SYNE1	CCDS5236.1	TNNI3	NMOOO363
SLC6A17	NM_001010898	SYNE1	CCDS5237.1	TNR	CCDS1318.1
3LC6A2	CCDS 10754.1	SYNE2	CCDS9761.1	TOR3A	CCDS1329.1
SLC6A3	CCDS3 863.1	SYP	CCDS14321.1	TP53	CCDS11118.1
SLC9A5	NM_004594	SYT1	CCDS9017.1	TP53BP1	CCDS 10096.1
3LCO1A2	CCDS8686.1	SYT6	CCDS871.1	TPO	CCDS 1642.1
SLCO1B1	CCDS8685.1	SYT7	NM 004200	TREH	NM 007180
SLCO1C1	CCDS8683.1	T	CCDS5290.1	TRERF1	CCDS4867.1
3LCO4C1	NM_180991	TAF1B	NM 005680	TRIM37	NM 001005207
SLITRK2	CCDS14680.1	TAF1L	NM 153809	TRIM58	CCDS1636.1
SLETRK3	CCDS3197.1	TAF4	NM_0O3185	TRPM1	CCDS 10024.1
3LETRK5	CCDS9465.1	TAS2R41	NM 176883	TRPM2	CCDS13710.1
SMAD3	CCDS 10222.1	TATDN2	NM 014760	TRPM3	CCDS6634.1
SMAD4	CCDS11950.1	TBC1D14	CCDS3394.1	TSC2	CCDS10458.1
SMARCA4	CCDS12253.1	TBX15	NM 152380	TSP-NY	CCDS9237.1
SMOC1	CCDS9798.1	TBX18	ENST00000330469	TSTA3	CCDS6408.1
SMTN	CCDS13886.1	TBX5	CCDS9173.1	TTBK2	NM_173500
SN	CCDS 13060.1	TBX6	CCDS 10670.1	TTC12	CCDS8360.1
SNCAIP	CCDS4131.1	TCEB3B	CCDS11932.1	TTC21B	NM 024753
SNRPC	NM_OO3O93	TCFL1	CCDS989.1	TTC24	ENST00000340086
SNX16	CCDS6234.1	TDRD7	CCDS6725.1	TTF1	CCDS6948.1
SNX26	CCDS12477.1	TENC1	CCDS8842.1	TTK	CCDS4993.1
SORL1	CCDS8436.1	TESSP2	NM_182702	TTN	NM_133378
SOX3	CCDS14669.1	TEX14	NM 198393	TTN	NM 133437
SP8	CCDS5372.1	TFCP2L1	CCDS2134.1	TUBB3	CCDS10988.1
SPAP1	CCDS1168.1	TFF2	CCDS 13684.1	TXNDC6	CCDS3099.1
SPATA13	ENST00000360220	TFPI2	CCDS5632.1	UBE1L	CCDS2805.1
SPINLW1	CCDS13359.1	TFR2	NM 003227	UBE2M	CCDS12987.1
SPTAN1	CCDS6905.1	TFSM1_HUMAN	ENST00000314720	UBQLN4	CCDS1127.1
SPTBN2	CCDS8150.1	TG	NM 003235	UBR2	CCDS4870.1
SR140HUMAN	ENST00000319822	TGFBR2	CCDS2648.1	UBXD7	ENST00000296328
SRCRB4D	CCDS5585.1	TGIF2	CCDS 13278.1	UCP3	CCDS8229.1
SRRM2	NMO16333	THNSL1	CCDS7147.1	ULBP1	CCDS5223.1
SST	CCDS3288.1	THSD7B	ENST00000272643	UNC13C	ENST00000260323
ST6GAL2	CCDS2073.1	TIMELESS	CCDS8918.1	USP20	NM_001008563
ST6GALNAC5	CCDS673.1	TJP1	NM 175610	USP31	CCDS10607.1
ST8SIA5	CCDS11930.1	TLL2	CCDS7449.1	USP38	CCDS3758.1
STAB1	NM_015136	TM7SF4	CCDS6301.1	USP42	NM_032172

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Gene Symbol UTRN	Accession ID NM 007124	Gene Symbol ZNF423	Accession ID NM 015069
VDAC2	CCDS7348.1	ZNF443	NM_OO5815
VGCNL1	CCDS9498.1	ZNF451	CCDS4960.1
VIM	CCDS7120.1	ZNF507	NM014910
VIT	NM_053276	ZNF537	CCDS 12421.1
VLDLR	CCDS6446.1	ZNF560	CCDS12214.1
VMD2L1	NM 017682	ZNF614	CCDS12847.1
VPS13A	CCDS6655.1	ZNF638	CCDS1917.1
VPS13D	NM018156	ZNF645	CCDS14205.1
VPS 16	CCDS13036.1	ZNF648	ENST00000339948
VPS39	CCDS 10083.1	ZNF682	NM_033196
VSIG1	CCDS14535.1	ZYGI IB	NM 024646
VWF	CCDS8539.1
WASF3	CCDS9318.1	Note: Gene symbols are standard
WBSCR14	CCDS5553.1	symbols assigned by Entrz Gene
WBSCR17	CCDS5540.1	(http://www.ncbi.nlm.nih.gov/sites/ent
WDR1	NM_005112	rez?db=gene). Accession IDs
WDR17	CCDS3825.1	“NM_XXXX” are	uniquely assigned

WDR27	NM 182552
WDR42B	ENST00000329763
WDR44	CCDS14572.1
WHSC1	CCDS3357.1
WIRE	CCDS11364.1
WNT9A	NMOO3395
WRNIP1	CCDS4475.1
XKR4	NM_052898
XPNPEP1	CCDS7560.1
XPO7	NM 015024
XR_017918.1	ENST00000258651
XYLT2	CCDS11563.1
YLPM1	ENST00000238571
YN002_HUMAN	ENST00000334389
ZAN	NM 173059
ZBTB24	NM 014797
ZBTB33	CCDS14596.1
ZBTB7	CCDS12119.1
ZC3H12B	NM 001010888
ZC3HDC7	CCDS10550.1
ZDHHC4	CCDS5352.1
ZFHX1B	CCDS2186.1
ZFP36	CCDS12534.1
ZHX3	CCDS13315.1
ZIM3	NM 052882
ZMAT4	NM_024645
ZNF133	CCDS13134.1
ZNF136	NM 003437
ZNF148	CCDS3031.1
ZNF238	CCDS 1623.1
ZNF253	ENST00000327867
ZNF31	NM_145238
ZNF333	CCDS 12316.1
ZNF334	NM 199441
ZNF365	CCDS7264.1

to each gene by National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/sites/ent rez?db=nuccore). Accession IDs “CCDSXXXX” are uniquely assigned to individual genes by National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/CCDS/) . Accession IDs “ENSTXXXXXXXXXXX” are uniquely assigned to individual genes by Ensembl (http://www.ensembl.org/index.html).

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'able 14. Genes containing	Gene Symbol	Accession ID	Gene Symbol	Accession ID
omatic mutations in breast	AP1M1	NM_032493.2	BLRl	NM_001716.2
ancer adapted from the	AP3B2	NM_004644	BMP1	NM_006129.2
aper by Wood et. al. (Wood t al., 2007).	APBB1 APC2 APCS	NM_145689 NM_005883.1 NM_001639.2	BOC BRCA1 BRCA2	NM_033254.2 NM_007296.1 NM_000059.1
Gene Symbol ABCA12	Accession ID NM_173076	APOC4 APOL1	NM_001646.1 NM_145343.1	BSPRY C10orf30	NM_017688 NM_152751.1
ABCA3	NM_001089.1	APPL	NM_012096.1	C10orf38	NM_001010924
ABCA4	NM_000350.1	APXL	NM_001649.2	C10orf39	NM_194303.1
ABCB10	NM_012089.1	AQP8	NM_001169.2	C10orf45	NM_031453.2
ABCB6	NM_005689.1	ARC	NM_015193	C10orf54	NM_022153
ABCB8	NM_007188.2	ARFGAP3	NM_014570.3	C10orf56	NM_153367.1
ABL2	NM_007314	ARFGEF2	NM_006420.1	C10orf64	NM_173524
ABLIM1	NM_002313.4	ARFRP1	NM_003224.2	Cllorf37	NM_001007543
ABP1	NM_001091	ARHGAP11A	NM_014783.2	Cllorf9	NM_013279
ACADM	NM_000016.2	ARHGAP25	NM_001007231	C13orf24	NM_006346
ACO2	NM_001098.2	ARHGEF4	NM_015320.2	C14orfl00	NM_016475
ACY1	NM_000666.1	ARID IB	NM_017519.1	C14orfl01	NM_017799.2
ADAM 12	NM_003474.2	ARRB1	NM_020251	C14orfl21	NM_138360
AD AMTS 16	NM_139056	ARRDC3	NM_020801	C14orfl55	NM_032135.2
AD AMTS 19	NM_133638.1	ARV1	NM_022786.1	C14orfl61	NM_024764
ADAR	NM_001111.2	ASB11	NM_080873.1	C14orf21	NM_174913.1
ADH1B	NM_000668	ASGR1	NM_001671.2	C14orl29	NM_181814.1
ADHFE1	NM_144650.1	ASL	NM_000048.2	CI4oiT46	NM_001024674
ADRA1A	NM_033302.1	ASTN2	NM_014010.3	C17orf47	NM_001038704
AEGP	NM_206920.1	ATCAY	NM_033064	C17orf64	NM_181707
AGBL4	NM_032785	ATF2	NM_001880.2	C18orfl9	NM_152352.1
AGC1	NM_001135	ATN1	NM_001940	C19orf28	NM_174983
AGRN	NM_198576	ATP10A	NM_024490	C19orf6	NM_033420.2
AHRR	NM_020731	ATP12A	NM_001676	Clorfl90	NM_001013615
AHSA2	NM_152392.1	ATP2A3	NM_174955.1	Clorf2	NM_006589.2
AIM1	NM_001624	ATP6AP1	NM_001183	C1QB	NM_000491.2
AKAP6	NM_004274.3	ATP6V0B	NM_004047.2	C20orfl03	NM_012261.2
AKAP8	NM_005858.2	ATP8B1	NM_005603.1	C20orfl21	NM_024331.2
AKAP9	NM_005751.3	ATP8B4	NM_024837	C20orfl61	NM_033421.2
ALCAM	NM_001627	ATRN	NM_139321.1	C20orfl77	NM_022106.1
ALMS1	NM_015120	ATXN2	NM_002973	C20orf23	NM_024704.3
ALS2	NM_020919	AVPI1	NM_021732.1	C20orf44	NM_018244.3
ALS2CL	NM_147129.2	AVPR2	NM_000054.2	C22orfl9	NM_003678.3
ALS2CR12	NM_139163.1	B3GALNT2	NM_152490.1	C4orfl4	NM_032313.2
ALS2CR19	NM_152526	B3GALT4	NM_003782	C5orfl4	NM_024715.2
AMFR	NM_001144.3	BAI1	NM_001702	C6orfl02	NM_145027.3
AMIGO 1	NM_020703	BAP1	NM_004656.2	C6orfl45	NM_183373.2
AMOTL1	NM_130847	BAT2	NM_080686.1	C6orfl74	NM_001012279
AMPD2	NM_139156.1	BAT3	NM_080703.1	C6orf204	NM_206921.1
AMPD2	NM_004037.5	BAZ1A	NM_013448.2	C6orf21	NM_001003693
ANAPC5	NM_016237.3	BAZ1B	NM_032408.1	C6orl213	NM_001010852
ANK1	NM_020476.1	BC002942	NM_033200.1	C6orf31	NM_030651.2
ANK2	NM_001148.2	BCAR1	NM_014567.2	C7orfll	NM_138701.1
ANKRD28	NM_015199	BCCIP	NM_016567.2	C9orfl26	NM_173690
ANKRD29	NM_173505.1	BCL11A	NM_018014.2	C9orf37	NM_032937
ANKRD30A	NM_052997.1	BCORL1	NM_021946.2	C9orf67	NM_032728.2
ANKRD5	NM_198798.1	BGN	NM_001711.3	CACNA1B	NM_000718

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
CACNA1F	NM_005183	COL11A1	NM_001854.2	DIP2B	NM_173602
□ACNA1G	NM_198385	COL12A1	NM_004370	DKFZP564B1023	NM_031306.1
CACNA1H	NM_021098	COL19A1	NM_001858.3	DKFZP564J102	NM_001006655
CACNA1I	NM_001003406	COL4A4	NM_000092	DKFZp761I2123	NM_031449
□ACNA2D3	NM_018398	COL7A1	NM_000094.2	DKFZp779B1540	NM_001010903
CAMTA1	NM_015215	COMMD7	NM_053041	DKK3	NM_015881.4
CAPN11	NM_007058	COPG	NM_016128	DLEC1	NM_007335.1
□BFB	NM_001755.2	COQ9	NM_020312	DMD	NM_004006.1
CCDC16	NM_052857	CP A3	NM_001870.1	DNAH17	NM_003727
CCDC18	NM_206886	CPAMD8	NM_015692	DNAH5	NM_001369.1
□CDC66	NM_001012506	CPEB1	NM_030594	DNAH9	NM_001372.2
CD2	NM_001767.2	CPS1	NM_001875.2	DNAJA3	NM_005147.3
CD74	NM_001025159	CPSF3	NM_016207.2	DNAJA5	NM_194283.1
□D97	NM_001784	CROCC	NM_014675	DNAJC10	NM_018981
CDC27	NM_001256.2	CRR9	NM_030782.2	DNAJC13	NM_015268
CDH10	NM_006727.2	CRSP2	NM_004229.2	DNASE1L3	NM_004944.1
□1)1120	NM.031891.2	CRTC1	NM_025021	DNM2	NM_004945
CDH8	NM_001796.2	CRX	NM_000554.2	DNM3	NM_015569
CDKL2	NM_003948.2	CRYAA	NM_000394.2	DOCK1	NM_001380
□DON	NM.016952.2	CSEN	NM_013434.3	DPAGT1	NM_001382.2
CDS1	NM_001263.2	CSMD1	NM_033225	DPAGT1	NM_203316.1
CENPE	NM_001813	CSMD3	NM_198123.1	DPP10	NM_020868
□ENTB1	NM_014716.2	CSNK1D	NM_001893.3	DPP6	NM_130797
CENTD3	NM.022481.4	CSPP1	NM_024790	DPYD	NM_000110
CENTG1	NM_014770.2	CST4	NM_001899.2	DRIM	NM_014503.1
□EP290	NM_025114	CTF8	NM_001039690	DSCR6	NM_018962.1
□FHL5	NM_030787.1	CTNNA1	NM_001903	DSG2	NM_001943
□FL2	NM_138638.1	CTNNA2	NM_004389	DTNA	NM_032978.4
□GI-14	NM_015944.2	CTNND1	NM_OO1331	DTX3L	NM_138287.2
□GI-37	NM_016101.2	CUBN	NM_001081.2	DUOX1	NM_017434
□HD1	NM_001270	CUTC	NM_015960.1	DVL3	NM_004423.3
□HD5	NM_015557.1	CUTL1	NM_001913.2	DYSF	NM_003494.2
□HD7	NM_017780	CUTL2	NM_015267	ECT2	NM_018098.4
□HD8	NM_020920	CYP1A1	NM_000499.2	EDEM1	NM_014674
CHD9	NM_025134	CYP1A2	NM_000761	EDNRA	NM_001957.1
CHRND	NM_000751.1	CYP26A1	NM_000783.2	EEF1G	NM_001404
CIC	NM_015125.2	CYP2D6	NM_000106	EGFL6	NM_015507.2
CLCA2	NM_006536.3	CYP4A22	NM_001010969	EHBP1	NM_015252.2
CLCN1	NM_000083.1	DACH1	NM_080759	EHMT1	NM_024757.3
CLCN3	NM_001829	DAZAP1	NM_018959.2	EIF4A2	NM_001967.2
CLEC6A	NM_001007033	DBN1	NM_004395.2	EIF4B	NM_001417
CLSPN	NM_022111.2	DC2	NM_021227.2	EIF5	NM_183004.3
CLUAP1	NM_015041	DDO	NM_003649.2	ELA1	NM_001971.3
CMYA1	NM_194293.2	DDX10	NM_004398.2	ELAVL3	NM_001420
CMYA4	NM_173167.1	DDX18	NM_006773.3	ENPEP	NM_001977.2
CNGA2	NM_005140.1	DDX3X	NM_024005.1	EOMES	NM_005442.2
CNGB1	NM_001297	DEFB128	NM_001037732	EP400	NM_015409
CNNM4	NM_020184.2	DENND2A	NM_015689	EPC2	NM_015630
CNTN3	NM_020872	DGKB	NM_004080	ERCC3	NM_000122.1
CNTN5	NM_014361	DGKE	NM_003647.1	ERCC6	NM_000124.1
CNTN6	NM_014461.2	DGKG	NM_001346.1	EREG	NM_001432.1
COG3	NM_031431.2	DHX32	NM_018180.2	ETV5	NM_004454
COH1	NM_017890.3	DIP	NM_015124	EVI2A	NM_001003927

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
EVI5	NM_005665	FLJ34521	NM_001039787	GOLGA7	NM_016099
EXOC2	NM_018303	FLJ36180	NM_178556.3	GOLGB1	NM_004487.1
EXOC5	NM_006544	FLJ36748	NM_152406	GOLPH4	NM_014498.2
EXOSC3	NM_016042	FLJ40342	NM_152347.3	GORASP2	NM_015530
FAAH	NM_001441.1	FLJ40869	NM_182625.2	GP5	NM_004488.1
FABP4	NM_001442.1	FLJ41821	NM_001001697	GPC1	NM_002081.1
FAM44A	NM_148894.1	FLJ45455	NM_207386	GPC2	NM_152742.1
FAM47B	NM_152631.1	FLJ46321	NM_001001670	GPHB5	NM_145171
FAM80B	NM_020734	FLJ46354	NM_198547.1	GPNMB	NM_002510.1
FANCA	NM_000135	FLJ46481	NM_207405.1	GPR115	NM_153838.1
FANCM	NM_020937	FLJ90579	NM_173591.1	GPR45	NM_007227.3
FARP1	NM_005766.1	FLNA	NM_001456	GPR7	NM_005285.1
FBXO40	NM_016298	FLNB	NM_001457.1	GPR81	NM_032554.2
FBXO8	NM_012180.1	FLNC	NM_001458	GRIK2	NM_021956.2
FBXW11	NM_012300	FMNL3	NM_175736	GRIK3	NM_000831.2
FCHO1	NM_015122	FMOD	NM_002023	GRIN2C	NM_000835
FCMD	NM.006731.1	FN1	NM_002026.2	GRIN2D	NM_000836.1
FCRH3	NM_052939.2	FNDC3B	NM_022763.2	GRIP API	NM_207672
FEM1C	NM_020177.2	FOLR2	NM_000803.2	GRM6	NM_000843.2
FER1L3	NM_133337	FOXP2	NM_014491.1	GSDML	NM_018530.1
FGD3	NM_033086	FOXP4	NM_138457.1	GSN	NM_000177.3
FGD6	NM_018351	FREM1	NM_144966	GTF2A1	NM_015859.2
FGFR2	NM_022970.1	FRMPD1	NM_014907.1	GTF3C1	NM_001520
FHOD1	NM_013241.1	FUCA1	NM_000147.2	GUCY2F	NM_001522.1
FHOD3	NM_025135	FUS	NM_004960.1	HADHB	NM_000183.1
FLG2	NM_001014342	FXR1	NM_005087.1	HCN3	NM_020897.1
FLJ10241	NM_018035	G3BP2	NM_203505.1	HDAC4	NM_006037.2
FU 10292	NM_018048.2	G6PC	NM_000151.1	HDAC7A	NM_015401.1
FLJ10324	NM_018059	GA17	NM_006360.2	HDLBP	NM_203346.1
FLJ10458	NM_018096.2	GAB1	NM_002039.2	HEBP1	NM_015987
FU 10726	NM_018195.2	GABRA4	NM_000809.2	HEL308	NM_133636.1
FLJ10874	NM_018252.1	GABRP	NM_014211.1	HIST1H4L	NM_003546.2
FLJ13089	NM_024953.2	GALK2	NM_001001556	HIST2H2AB	NM_175065.2
FLJ13231	NM_023073	GALNT17	NM_001034845	HK3	NM_002115.1
FLJ13479	NM_024706.3	GALNT5	NM_014568.1	HLCS	NM_000411.4
FLJ13868	NM_022744.1	GALNTL2	NM_054110	HM13	NM_030789.2
FLJ14503	NM_152780.2	GARNL1	NM_194301	HMG2L1	NM_001003681
FLJ14624	NM_032813.1	GDF6	NM_001001557	HOMER2	NM_199331
FLJ16331	NM_001004326	GGA1	NM_013365.2	HOOK1	NM_015888.3
FLJ20152	NM_019000	GGA3	NM_014001.2	HOOK2	NM_013312
FLJ20184	NM_017700.1	GIMAP1	NM_130759.2	HOOK3	NM_032410.2
FLJ20422	NM_017814.1	GIMAP8	NM_175571	HOXA3	NM_153631.1
FLJ20584	NM_017891.2	GIOT-1	NM_153257	HOXA4	NM_002141.2
FLJ20604	NM_017897.1	GIPC3	NM_133261	HS3ST4	NM_006040
FLJ21839	NM_021831.3	GJA8	NM_005267	HSD11B1	NM_181755.1
FLJ21945	NM_025203.1	GJB1	NM_000166.2	HSD17B8	NM_014234.3
FLJ23584	NM_024588	GKN1	NM_019617.2	HSHIN1	NM_199324.1
FLJ25955	NM_178821.1	GLG1	NM_012201	HSPA14	NM_016299.1
FLJ31413	NM_152557.3	GLI1	NM_005269.1	HSPA1B	NM_005346
FLJ32115	NM_152321.1	GLT25D2	NM_015101.1	HSPC049	NM_014149
FLJ32363	NM_198566.1	GMCL1L	NM_022471.2	HTF9C	NM_182984.2
FLJ32440	NM_173685.1	GNB1L	NM_053004.1	HUMCYT2A	NM_015848.1
FLJ32830	NM_152781.1	GNPAT	NM_014236.1	HUWE1	NM_031407

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
1CAM5	NM_003259.2	KIAA1324	NM_020775.2	LOC652968	NM_001037666
1FNA2	NM_000605.2	KIAA1377	NM_020802	LOC88523	NM_O33111
EFNBl	NM_002176.1	KIAA1414	NM_019024	LOC90529	NM_178122.2
[KBKAP	NM_003640.2	KIAA1632	NM_020964.1	LOC91461	NM_138370
[KB KB	NM_001556.1	KIAA1797	NM_017794	LOXL2	NM_002318
1L1RAPL2	NM_017416.1	KIAA1826	NM_032424	LPO	NM_006151
EL7R	NM_002185.2	KIAA1914	NM_001001936	LRBA	NM_006726.1
[NA	NM_032727.2	KIAA1946	NM_177454	LRRC16	NM_017640
ΕΝΉΒΕ	NM_031479.3	KIBRA	NM_015238.1	LRRC4	NM_022143.3
1PLA2(GAMMA)	NM_015723	KIF14	NM_014875	LRRC43	NM_152759
1PO7	NM_006391	KIR2DS4	NM_012314.2	LRRC7	NM_020794.1
[QSEC2	NM_015075	KLHL10	NM_152467	LRRFIP1	NM_004735.1
[RF8	NM_002163.1	KLHL15	NM_030624	LUZP5	NM_017760
[RS4	NM_003604.1	KLK15	NM_017509.2	LYST	NM_000081
[RTA2	NM_031281.1	KPNA5	NM_002269.2	LYST	NM_001005736
1TGA9	NM_002207.1	KRTAP10-8	NM_198695.1	LZTS2	NM_032429.1
[TGAE	NM_002208	KRTAP20-1	NM_181615.1	MACF1	NM_012090.3
[TGAL	NM_002209	KTN1	NM_182926.1	MAGEA1	NM_004988.3
1TGB2	NM.000211.1	LAMA1	NM_005559	MAGEA4	NM_002362.3
1TPR1	NM_002222	LAMA2	NM_000426.2	MAGEB10	NM_182506
[TR	NM_180989.3	LAMA4	NM_002290	MAGEC2	NM_016249.2
1ARID1B	NM_006618	LAMB4	NM_007356	MAGED2	NM_201222.1
IMJD1A	NM_018433.3	LAP IB	NM_015602.2	MAGEE 1	NM_020932.1
1MJD1C	NM_004241	LDHB	NM_002300.3	MAGI1	NM_173515.1
TUP	NM.021991.1	LEPREL1	NM_018192.2	MANEA	NM_024641.2
KCNA5	NM_002234.2	LGALS2	NM_006498.1	MAOA	NM_000240.2
KCNC2	NM_139136.2	LHCGR	NM_000233.1	ΜΑΡΙΑ	NM_002373
KCNJ1	NM_000220.2	LIP8	NM_053051.1	MAP3K6	NM_004672.3
KCNJ15	NM_170737.1	LIPE	NM_005357.2	MAPK13	NM_002754.3
KCNQ3	NM_004519	LLGL1	NM_004140	MAPKBP1	NM_014994
KEAP1	NM_203500.1	LMO6	NM_006150.3	MASP1	NM_001879
ΚΙΛΛ0Ι00	NM_014680	LOCI 12703	NM_138411	MAZ	NM_002383
KIAA0143	NM_015137	LOC113179	NM_138422.1	MCAM	NM_006500
ΚΙΑΛ0256	NM_014701	LOCI 13828	NM_138435.1	MCART1	NM_033412.1
KIAA0284	NM_015005	LOCI 23 876	NM_001010845	MCF2L2	NM_015078.2
KIAA0367	NM_015225	LOCI 26248	NM_173479.2	MCOLN1	NM_020533.1
KIAA0427	NM_014772.1	LOC200420	NM_145300	MDC1	NM_014641
KIAA0467	NM_015284	LOC220929	NM_182755.1	MED12	NM_005120
KIAA0513	NM_014732	LOC253012	NM_198151.1	MEF2C	NM_002397
KIAA0528	NM_014802	LOC255374	NM_203397	MFAP5	NM_003480.2
KIAA0664	NM_015229	LOC283849	NM_178516.2	MGC11332	NM_032718.2
KIAA0672	NM_014859	LOC339123	NM_001005920	MGC17299	NM_144626.1
KIAA0676	NM_015043.3	LOC339745	NM_001001664	MGC21688	NM_144635.3
KIAA0703	NM_014861	LOC340156	NM_001012418	MGC24047	NM_178840.2
KIAA0774	NM_001033602	LOC374955	NM_198546.1	MGC27019	NM_144705.2
KIAA0789	NM_014653	LOC388595	NM_001013641	MGC33212	NM_152773
KIAA0863	NM_014913	LOC388915	NM_001010902	MGC33370	NM_173807.2
KIAA0913	NM_015037	LOC389151	NM_001013650	MGC33657	NM_001029996
KIAA0934	NM_014974.1	LOC3 89549	NM_001024613	MGC34837	NM_152377.1
KIAA0999	NM_025164.3	LOC440925	NM_001013712	MGC42174	NM_152383
KIAA1012	NM_014939.2	LOC440944	NM_001013713	MGC5297	NM_024091.2
KIAA1117	NM_015018.2	LOC441070	NM_001013715	MIA2	NM_054024.3
KIAA1161	NM_020702	LOC646870	NM_001039790	MICAL1	NM_022765.2

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
MICAL-Ll	NM.033386.1	NFl	NM_000267.1	OSBP2	NM_030758
MKLN1	NM.013255	NF2	NM_000268.2	OSBPL11	NM_022776.3
MLL4	NM.014727	NFASC	NM_015090	OTC	NM_000531.3
MLLT2	NM_005935.1	NFIX	NM_002501	OTOF	NM_194323.1
MMP10	NM.002425.1	NFKB1	NM_003998.2	P15RS	NM_018170.2
MMP15	NM_002428.2	NFKBIA	NM_020529.1	PADI3	NM_016233.1
MOGAT1	NM.058165	NFKBIE	NM_004556	PADI6	NM_207421
MOSPD1	NM.019556.1	NFYC	NM_014223.2	PANX2	NM_052839.2
MPFL	NM_001025190	NGLY1	NM_018297	PAPPA2	NM_020318
MRE11A	NM_005590.2	NHS	NM_198270.2	PARP1	NM_001618.2
MSI1	NM.002442.2	NID2	NM_007361.2	PCDH19	NM_020766
MTA1	NM_004689	NIPBL	NM_133433.2	PCDH20	NM_022843.2
MTAC2D1	NM_152332.2	NOD27	NM_032206.2	PCDH8	NM_002590.2
MTL5	NM.004923.2	NOS2A	NM_000625.3	PCDHA10	NM_031859
MTMR3	NM_021090.2	NOTCH 1	NM_017617	PCDHA11	NM_031861
MTMR8	NM_017677.2	NOTCH4	NM_004557	PCDHA5	NM_031501
MUC16	NM.024690	NOX5	NM_024505	PCDHB15	NM_018935.2
MUC2	NM_002457	NRCAM	NM_005010.2	PCDHGA1	NM_031993
MUF1	NM_006369.3	NRK	NM_198465	PCDHGA3	NM_032011
MULK	NM_018238.2	NRXN3	NM_004796.3	PCDHGA6	NM_032086
MYBPC2	NM_004533	NUFIP2	NM_020772	PCDHGB1	NM_032095
MYCBP2	NM_015057	NUP133	NM_018230.2	PCDHGB5	NM_032099
MYH1	NM.005963.2	NUP188	NM_015354	PCM1	NM_006197
MYH7B	NM_020884	NUP205	NM_015135	PCNT	NM_006031
MYH9	NM_002473.2	NUP214	NM_005085.2	PDCD11	NM_014976
MYLC2PL	NM_138403	NUP98	NM_016320.2	PDCD4	NM_014456.3
MYO15A	NM.016239	NXN	NM_022463.3	PDCD6	NM_013232.2
MYO18B	NM_032608	NYD-SP21	NM_032597	PDE2A	NM_002599.1
MYO1G	NM_033054	OATL1	NM_002536	PDLIM7	NM_005451.3
MYO7A	NM_000260	OBSCN	NM_052843.1	PDPR	NM_017990
VIYO9B	NM_004145	OCA2	NM_000275.1	PDZD7	NM_024895
MYOD1	NM_002478.3	ODZ1	NM_014253.1	PDZK2	NM_024791.2
MYR8	NM_015011	OR10A2	NM_001004460	PDZK4	NM_032512.2
MYST4	NM_012330.1	OR10H4	NM_001004465	PEBP4	NM_144962
N4BP2	NM_018177.2	OR12D3	NM_030959.2	PERI	NM_002616.1
NAG6	NM_022742	OR1J2	NM_054107	PER2	NM_022817.1
NALP1	NM_014922	OR1N1	NM_012363.1	PEX14	NM_004565
NALP14	NM_176822.2	OR1S1	NM_001004458	PFC	NM_002621.1
NALP8	NM_176811.2	OR2AK2	NM_001004491	PFKFB4	NM_004567.2
NALP9	NM_176820.2	OR2M4	NM_017504	PGBD3	NM_170753.1
NAV3	NM_014903	OR2W3	NM_001001957	PHACS	NM_032592.1
NCAM1	NM_000615	OR2W5	NM_001004698	PHC1	NM_004426.1
NCB5OR	NM_016230.2	OR4D2	NM_001004707	PHF19	NM_015651
NCOA6	NM_014071.2	OR52A1	NM_012375	PHF7	NM_016483.4
NDRG2	NM_201541.1	OR52H1	NM_001005289	PHKB	NM_000293.1
NDST1	NM_001543	OR56A1	NM_001001917	PIGN	NM_176787
NDUFA2	NM_002488.2	OR5H1	NM_001005338	PIGS	NM_O33198.2
NDUFA3	NM_004542.1	OR5J2	NM_001005492	PIK3C2G	NM_004570
NDUFA8	NM_014222.2	OR5M11	NM_001005245	PIK3CA	NM_006218
NEB	NM_004543	OR8B12	NM_001005195	PIK3R1	NM_181523.1
NEDD4	NM_198400.1	OR8D2	NM_001002918	PIK3R4	NM_014602.1
NEF3	NM_005382.1	OR8I2	NM_001003750	PKD1L1	NM_138295
NET1	NM_005863.2	OR9Q2	NM_001005283	PKD1L2	NM_052892

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
PKDREJ	NM_006071.1	PTRF	NM_012232.2	SAPSl	NM_014931
PKHD1L1	NM_177531	PURG	NM_013357.2	SATL1	NM_001012980
PKN1	NM_213560	PUS1	NM_025215.3	SBNO1	NM_018183.2
PLA2G4A	NM_024420.1	PUS7	NM_019042	SCARF2	NM_153334.3
PLB1	NM_153021	RAB41	NM_001032726	SCGB3A2	NM_054023.2
PLCB1	NM_015192.2	RABEP2	NM_024816	SCML1	NM_006746.2
PLCB2	NM_004573	RAC2	NM_002872.3	SCN2A2	NM_021007
PLCD3	NM_133373	RAI17	NM_020338.1	SCN3A	NM_006922
PLCG1	NM_002660.2	RANBP1	NM_002882.2	SCNN1B	NM_000336.1
PLD2	NM_002663.2	RANBP3	NM_007321	SCP2	NM_002979.2
PLEKHA8	NM_032639.2	RANBP3	NM_007322	SEC31L1	NM_014933.2
PLEKHG2	NM_022835	RAP1GA1	NM_002885.1	SEMA3A	NM_006080.1
PLOD1	NM_000302.2	RAPH1	NM_213589.1	SEMA4B	NM_198925
PLS3	NM_005032.3	RARG	NM_000966.3	SEMA4G	NM_017893.2
PLXNB1	NM_002673.3	RASAL2	NM_170692.1	SEMA5B	NM_018987.1
PNCK	NM_198452.1	RASGRF2	NM_006909.1	SEMA6D	NM_153616
PNLIPRP1	NM_006229.1	RASL10B	NM_033315.2	SEMA7A	NM_003612.1
PNPLA1	NM_001039725	RBAF600	NM_020765.1	SEPHS2	NM_012248
PODXL	NM_001018111	RBM25	NM_021239	SERPINB1	NM_030666.2
POLH	NM_006502.1	RCE1	NM_005133.1	SERPINB11	NM_080475
POLR2F	NM_021974.2	RFC4	NM_181573.1	SERPINE2	NM_006216.2
POP1	NM_015029.1	RFX2	NM_000635.2	SF3B1	NM_012433
POU2F1	NM_002697.2	RG9MTD2	NM_152292.2	SF3B2	NM_006842
POU4F2	NM_004575	RGL1	NM_015149.2	SFRS1	NM_006924.3
PP	NM_021129.2	RGS22	NM_015668	SFRS16	NM_007056.1
PPAPDC1A	NM_001030059	RHAG	NM_000324.1	SGKL	NM_013257.3
PPFIBP2	NM_003621	RHD	NM_016124.2	SH2D3A	NM_005490.1
PPHLN1	NM_201439.1	RIF1	NM_018151.1	SH3RF1	NM_020870
PPM1E	NM_014906.3	RIMS1	NM_014989	SHCBP1	NM_024745.2
PPM IF	NM_014634.2	RIMS2	NM_014677	SIGLEC5	NM_003830
PPP1R12A	NM_002480	RLTPR	NM_001013838	SIPA1L1	NM_015556.1
PPP1R3A	NM_002711.2	RNF123	NM_022064	SIX4	NM_017420.1
PRDM13	NM_021620	RNF127	NM_024778.3	SKIP	NM_016532.2
PRDM4	NM_012406.3	RNF149	NM_173647.2	SKIV2L	NM_006929.3
PRDX5	NM_012094.3	RNU3IP2	NM_004704.2	SLAMF1	NM_003037.1
PRKAA1	NM_006251.4	ROBO3	NM_022370	SLC12A3	NM_000339.1
PRKAA2	NM_006252.2	ROR1	NM_005012.1	SLC16A2	NM_006517.1
PRODH	NM_016335.2	RP1L1	NM_178857	SLC17A6	NM_020346.1
PRPF39	NM_017922.2	RPGRIP1	NM_020366	SLC22A2	NM_003058.2
PRPF4B	NM_176800.1	RPL3	NM_000967.2	SLC22A9	NM_080866.2
PRPS1	NM_002764.2	RPRC1	NM_018067	SLC25A30	NM_001010875
PRPS1L1	NM_175886	RPS26	NM_001029	SLC35A2	NM_005660.1
PRRG1	NM_000950.1	RPS6KA3	NM_004586.1	SLC35F1	NM_001029858
PRSS7	NM_002772.1	RPS9	NM_001013.2	SLC38A3	NM_006841
PSD	NM_002779	RPUSD4	NM_032795.1	SLC39A12	NM_152725.1
PSME4	NM_014614	RREB1	NM_001003699	SLC4A3	NM_005070.1
PSPC1	NM_018282	RSN	NM_002956.2	SLC6A3	NM_001044.2
PSRC2	NM_144982	RTP1	NM_153708.1	SLC6A5	NM_004211.1
PTD004	NM_013341.2	RTTN	NM_173630	SLC7A7	NM_003982.2
PTHLH	NM_198964.1	RUFY1	NM_025158.2	SLC8A3	NM_033262.3
PTPN14	NM_005401.3	RYR1	NM_000540	SLC8A3	NM_182932.1
PTPN6	NM_080548	RYR2	NM_001035	SLC9A10	NM_183061
PTPRC	NM_002838.2	SAMD9	NM_017654	SLC9A2	NM_003048.3

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
SLCO2B1	NM_007256.2	TACC2	NM_206862.1	TREMLl	NM_178174.2
SLFN13	NM_144682	TAF1	NM_004606.2	TREML4	NM_198153
SLICK	NM_198503.2	TAF1B	NM_005680	TRIAD3	NM_207116
SMARCAL1	NM_014140.2	TA-KRP	NM_032505.1	TRIF	NM_182919.1
SMC4L1	NM_005496.2	TAS2R13	NM_023920.1	TRIM25	NM_005082.3
SMC6L1	NM_024624.2	TAX1BP1	NM_006024.4	TRIM29	NM_012101.2
SMOX	NM_175839.1	TBC1D19	NM_018317.1	TRIM36	NM_018700.2
SN	NM_023068.2	TBC1D2B	NM_015079	TRIOBP	NM_001039141
SNTG2	NM_018968	TBX1	NM_005992.1	TRIP 12	NM_004238
SNX25	NM_031953	TBXAS1	NM_001061.2	TRPC4	NM_016179.1
SOHLH1	NM_001012415	TCEAL5	NM_001012979	TRPM5	NM_014555
SORBS 1	NM_015385.1	TCF1	NM_000545.3	TSN	NM_004622
SORCS1	NM_052918.2	TCF7L1	NM_031283.1	TTC 15	NM_016030.5
SORL1	NM_003105.3	TCFL1	NM_005997.1	TTC21B	NM_024753
SOX13	NM_005686	TCP1	NM_030752.1	TTC3	NM_003316.2
SOX15	NM_006942	TCP10	NM_004610	TTC7A	NM_020458
SP11O	NM_004509.2	TDRD6	NM_001010870	TTN	NM_133378
SPAG6	NM_012443.2	TECTA	NM_005422.1	TXNDC3	NM_016616.2
SPATS2	NM_023071	TEK	NM_000459.1	UBE2I	NM_194261.1
SPCS2	NM_014752	TESK1	NM_006285.1	UBE2O	NM_022066
SPEN	NM_015001.2	TESK2	NM_007170	UGT1A9	NM_021027.2
SPG4	NM_014946.3	TEX 11	NM_031276	UNQ9356	NM_207410.1
SPINK5	NM_006846	TFAP2D	NM_172238.1	UQCR	NM_006830.2
SPO11	NM_012444.2	TG	NM_003235	USP29	NM_020903
SPOCD1	NM_144569.3	TGM3	NM_003245	USP34	NM_014709
SPTA1	NM_003126	THBS3	NM_007112.3	USP54	NM_152586.2
SPTAN1	NM_003127.1	THG-1	NM_030935.3	UTP14C	NM_021645
SPTBN1	NM_178313	TIAM2	NM_001010927	UTS2R	NM_018949.1
SPTLC1	NM_006415.2	TIFA	NM_052864	VAV3	NM_006113.3
SPTY2D1	NM_194285	TIMELESS	NM_003920.1	VEPH1	NM_024621.1
SREBF2	NM_004599.2	TLL1	NM_012464.3	VGCNF1	NM_052867.1
SRGAP3	NM_014850.1	TLN1	NM_006289	VWF	NM_000552.2
SSFA2	NM_006751.3	TLN2	NM_015059	WARS	NM_173701.1
SSNA1	NM_003731.1	TM4SF7	NM_003271.3	WBP4	NM_007187.3
ST8SIA3	NM_015879	TMED1	NM_006858.2	WBSCR28	NM_182504
STAB1	NM_015136	TMEM123	NM_052932	WDR48	NM_020839
STARD8	NM_014725.2	TMEM132B	NM_052907	WDR53	NM_182627.1
STAT1	NM_007315.2	TMEM28	NM_015686	WDR60	NM_018051
STAT4	NM_003151.2	TMEM37	NM_183240	WDSOF1	NM_015420
STATIP1	NM_018255.1	TMEM39A	NM_018266.1	WFDC1	NM_021197.2
STRBP	NM_018387.2	TMEM62	NM_024956	WNK1	NM_018979.1
STX12	NM_177424.1	TMEM63A	NM_014698	WNT2	NM_003391.1
STX5A	NM_003164.2	TMPRSS3	NM_024022.1	XAB2	NM_020196
SULF2	NM_018837.2	TMPRSS6	NM_153609.1	XBP1	NM_005080.2
SULT6B1	NM_001032377	TNFRSF25	NM_003790.2	XDH	NM_000379.2
SUPT3H	NM_181356	TNS	NM_022648.2	XKR7	NM_001011718
SURF1	NM_003172.2	TOPI	NM_003286.2	XPO5	NM_020750
SUSD3	NM_145006.2	TOP2B	NM_001068	XPO7	NM_015024
SUV39H2	NM_024670.3	TP53	NM_000546.2	YY2	NM_206923.1
SYNE2	NM_182914.1	TPM4	NM_003290.1	ZBTB3	NM_024784.2
SYT3	NM_032298.1	TPTE	NM_199261.1	ZBTB39	NM_014830
SYTL2	NM_032943	TRAD	NM_007064.1	ZCCHC14	NM_015144.1
TAC4	NM_170685	TREM1	NM_018643.2	ZCSF3	NM_181706.3

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
ZDHHC4	NM_018106.2	ZNF142	NM_005081	ZNF281	NM_012482.3
ΖΓΙΙΧ4	NM_024721	ZNF161	NM_007146	ZNF318	NM_014345.1
ZFP64	NM_199427.1	ZNF183	NM_006978.1	ZNF37A	NM_001007094
ZFYVE26	NM_015346.2	ZNF22	NM_006963.2	ZNF425	NM_001001661
ZIC3	NM_003413.2	ZNF25	NM_145011.2	ZNF432	NM_014650.2
ZNF10	NM_015394.4	ZNF267	NM_003414	ZNF436	NM_030634.1
ZNF124	NM_003431	ZNF277	NM_021994.1	ZNF529	NM_020951
ZNF532	NM_018181.3
ZNF541	NM_032255.1	ZNF674	NM_001039891
ZNF546	NM_178544.2	ZNF694	NM_001012981
ZNF548	NM_152909	ZNF707	NM_173831
ZNF569	NM_152484.2	ZNF75A	NM_153028.1
ZNF644	NM_201269.1	ZNHIT2	NM_014205.2
ZNF646	NM_014699.2

'ote: Gene symbols are standard /mhols assigned by Entrz Gene ittp://www.ncbi.nlm.nih.gov/sites/ent ;z?db=gene). Accession IDs

MX XXX” are uniquely assigned ) each gene by National Center for iotechnology Information (NCBI) ittp://www.ncbi.nlm.nih.gov/sites/ent ;z?db=nuccore)

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Gene Symbol

ABCA1

ABCA6

ABCB1

ABCB11

ABCB5

ABCC5

ABCD4

ABI3BP

ACACA

ACINI

ACSL4

ACSL5

Λ 1)026

ADAM 19

ADAM29

ADAM33

ADAM8

AD AMTS 1

ADAMTS15

ADAMTS18

ADAMTS20

ADAMTS20

ADAMTSL3

ADARB2

ADCY8

ADCY9

ADD3

ADORA1

AFMID

AGTPBP1

AIM1

AKAP12

AKAP3

AKAP6

AKAP9

ALDH1L1

ALG9

ALK

ALS2CR11

ALS2CR8

AMACO

AMOTL2

AMPD1

AMPD3

ANAPC4

ANK2

ANKFN1

ANKRD11

Accession

ID

NM_005502.2

NM_080284.2

NM_000927.3

NM_003742

NM_178559.3

NM_005688

NM_005050.1

NM_015429

NM_198839.1

NM_014977.1

NM_022977.1

NM_016234.3

NM_020683.5

NM_033274.1

NM_014269.2

NM_025220.2

NM_001109

NM_006988

NM_139055.1

NM_199355.1

NM_025003

NM_175851

NM_207517.1

NM_018702.1

NM_001115.1

NM_001116

NM_016824.2

NM_000674.1

NM_001010982

NM_015239.1

NM_001624

NM_005100.2

NM_006422.2

NM_004274.3

NM_005751.3

NM_012190.2

NM_024740

NM_004304

NM_152525.3

NM_024744

NM_198496.1

NM_016201

NM_000036.1

NM_000480.1

NM_013367.2

NM_001148.2

NM_153228

NM_013275

Gene Symbol

ANKRD26

APBB2

APC

APG5L

API5

APIN

APOB

APOB48R

AQR

ARAF

ARFGEF1

ARHGEF1

ARHGEF10

ARHGEF9

ARR3

ASCC3L1

ASE-1

AT ADI

ATP11A

ATP11C

ATP12A

ATP13A1

ATP13A5

ATP13A5

ATP6V1E1

ATP8A2

ATP8B4

AVPR1B

AZI1

BCAP29

BCAS2

BCL11B

BCL9

BICD1

BMP6

BMPR2

BPIL1

BRAF

BRF1

BRUNOL6

BTBD4

BTF3L4

C10orfl37

C10orf28

C10orf64

C10orf72

C12orfll

C13orf7

C14orfll5

C15orf2

C17orf27

C17orf46

C17orf49

Accession

ID

NM_014915

NM_173075

NM_000038.2

NM_004849.1

NM_006595

NM_017855.2

NM_000384.1

NM_182804

NM_014691

NM_001654

NM_006421.2

NM_199002.1

NM_014629

NM_015185

NM_004312.1

NM_014014.2

NM_012099.1

NM_032810.2

NM_032189

NM_173694.2

NM_001676

NM_020410

NM_198505

NM_198505

NM_001696.2

NM_016529

NM_024837

NM_000707

NM_001009811

NM_001008405

NM_005872.1

NM_022898.1

NM_004326

NM_001714.1

NM_001718.2

NM_001204

NM_025227.1

NM_004333.2

NM_001519.2

NM_052840.2

NM_025224.1

NM_152265

NM_015608.2

NM_014472

NM_173524

NM_144984.1

NM_018164.1

NM_024546

NM_018228.1

NM_018958.1

NM_020914

NM_152343

NM_174893

Gene Symbol

C18orf4

C1QR1

C20orf23

C21orfl8

C21orf29

C21orf88

C2orfl0

C2orfl6

C2orf33

C4BPA

C4orfl5

C6orfl91

C6orf29

C8B

C9orf21

Cab45

CACNA1A

CACNA1B

CACNA2D3

CACNB1

CACNB2

CAD

CAPN10

CAPN13

CAPN6

CARD 12

CBFA2T3

CCAR1

CCNB3

CD 109

CD248

CD99L2

CDC14A

CDH13

CDH18

CDH23

CDH6

CDKL5

CDO1

CDS1

CEACAM20

CENPF

CENPH

CENTB1

CENTB2

CENTD3

CGI-14

CHD7

CHD8

CHL1

CHR415SYT

CHST8

CINP

Accession

ID

NM_032160.1

NM_012072.2

NM_024704.3

NM_017438.1

NM_144991.2

NM_153754

NM_194250.1

NM_032266

NM_020194.4

NM_000715.2

NM_024511

NM_001010876

NM_025257.1

NM_000066

NM_153698

NM_016547.1

NM_000068

NM_000718

NM_018398

NM_199247.1

NM_201596.1

NM_004341.3

NM_023086.1

NM_144575

NM_014289.2

NM_021209

NM_005187.4

NM_018237.2

NM_033031.1

NM_133493.1

NM_020404.2

NM_134445.1

NM_003672.2

NM_001257

NM_004934.2

NM_022124

NM_004932.2

NM_003159.1

NM_001801.1

NM_001263.2

NM_198444

NM_016343

NM_022909.3

NM_014716.2

NM_012287

NM_022481.4

NM_015944.2

NM_017780

NM_020920

NM_006614.2

NM_001014372

NM_022467.3

NM_032630.2

138

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Gene Symbol

CIR

CLIC2

CLSTN2

CLSTN3

CMKOR1

CNKSR2

CNOT6L

CNTN1

CNTN4

COL12A1

COL3A1

COL4A6

CORO1B

CORO2B

CPAMD8

CPE

CPO

CRB1

CRNKL1

CSDA

CSE1L

CSMD1

CSMD3

CSNK1A1L

CTCFL

CTEN

CTNNA1

CTNND2

CTSH

CUBN

CUTL1

CX40.1

CXorf53

CYP4F8

DACT1

DBC1

DCC

DCHS1

DDEFL1

DDHD2

DDI1

DDIT3

DDN

DDX53

DEFA4

DEFB111

DENND1C

DEPDC2

DGCR2

DHRS2

DJ167A19.1

DKFZp761I2123

DLG3

Accession ID	Gene Symbol	Accession ID	Gene Symbol
NM_004882.3	DMD	NM_004021.1	FBXF2
NM_001289.3	DMD	NM_004006.1	FBXO30
NM_022131.1	DMRTA1	NM_022160.1	FBXW7
NM_014718.2	DNAH1	NM_015512	FCN1
NM_020311.1	DNAH11	NM_003777	FCN2
NM_014927.2	DNAH3	NM_017539.1	FERD3F
NM_144571	DNAH8	NM_001371.1	FGF13
NM_001843.2	DNAJC10	NM_018981	FGF14
NM_175613.1	DNAJC6	NM_014787	FHOD3
NM_004370	DNALI1	NM_003462.3	FIGN
NM_000090.2	DNAPTP6	NM_015535	FLJ10241
NM_001847.1	DNASE 1L3	NM_004944.1	FLJ10404
NM_020441.1	DPEP1	NM_004413.1	FLJ10490
NM_006091.1	DPP10	NM_020868	FLJ10521
NM_015692	DPYSL2	NM_001386.3	FLJ10560
NM_001873.1	DSCAML1	NM_020693.2	FLJ10665
NM_173077.1	DSTN	NM_006870.2	FLJ10996
NM_201253.1	DTNB	NM_183361	FLJ11000
NM_016652	DUSP21	NM_022076.2	FLJ12770
NM_003651.3	DUX4C	NM_001023569	FLJ13305
NM_001316.2	EDA	NM_001399.3	FLJ14803
NM_033225	EDD1	NM_015902	FLJ16171
NM_198123.1	EFS	NM_005864.2	FLJ16542
NM_145203.2	EIF2S2	NM_003908.2	FLJ20294
NM_080618.2	EIF4G1	NM_198241.1	FLJ20729
NM_032865.3	EML1	NM_004434	FLJ21019
NM_001903	EML2	NM_012155.1	FLJ21986
NM_001332.2	EN1	NM_001426.2	FLJ22679
NM_004390.2	ENPP2	NM_006209.2	FLJ25477
NM_001081.2	EPHA3	NM_005233.3	FLJ32252
NM_001913.2	EPHA4	NM_004438.3	FLJ32312
NM_153368.1	EPHA7	NM_004440.2	FLJ33534
NM_024332	EPHB1	NM_004441	FLJ34633
NM_007253	EPHB6	NM_004445.1	FLJ34922
NM_016651.4	ERCC6	NM_000124.1	FLJ35834
NM_014618.1	ESSPL	NM_183375	FLJ36119
NM_005215.1	ETAA16	NM_019002.2	FLJ38964
NM_003737.1	ETFDH	NM_004453.1	FLJ40142
NM_017707.2	EVC2	NM_147127.2	FLJ42418
NM_015214	EVL	NM_016337.1	FLJ43339
NM_001001711	EYA4	NM_004100.2	FLJ43980
NM_004083.3	EZH2	NM_004456.3	FLJ44653
NM_015086	F5	NM_000130.2	FLJ45273
NM_182699	F8	NM_000132	FLJ46082
NM_001925.1	FAM102B	NM_001010883	FLJ46154
NM_001037497	FAM19A5	NM_015381	FLNC
NM_024898	FAM26A	NM_182494	FMN2
NM_024870.2	FAM3A	NM_021806	FN1
NM_005137	FAM40A	NM_033088	FNDC1
NM_005794.2	FANCG	NM_004629.1	FOLH1
NM_018982.3	FAT	NM_005245	FRAS1
NM_031449	FBN1	NM_OOO138	FRAS1
NM_021120.1	FBN2	NM_001999	FRMPD2

Accession

ID

NM_012157.2

NM_032145.3

NM_033632.1

NM_002003.2

NM_004108.1

NM_152898.2

NM_033642.1

NM_175929.1

NM_025135

NM_018086.1

NM_018035

NM_019057

NM_018111

NM_018125.2

NM_018138.1

NM_018173.1

NM_019044.2

NM_018295.1

NM_032174.3

NM_032180

NM_032842

NM_001004348

NM_001004301

NM_017749

NM_017953.2

NM_024927.3

NM_024913

NM_032227.1

NM_199138.1

NM_182510

NM_144709.1

NM_182586.1

NM_152365.1

NM_152270.2

NM_178827.3

NM_153254.1

NM_173527

NM_207435.1

NM_001001695

NM_207380.1

NM_001004299

NM_001001678

NM_198461.1

NM_207417.1

NM_198462.1

NM_001458

NM_020066

NM_002026.2

NM_032532

NM_004476.1

NM_025074

NM_032863

NM_152428.2

139

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
FRMPD4	NM_014728	HS3ST4	NM_006040	KRTAP10-8	NM_198695.1
FRY	NM_023037	HSPG2	NM_005529	KSR2	NM_173598
FSTL5	NM_020116.2	HTR3C	NM_130770.2	LAMA1	NM_005559
FZD4	NM_012193.2	HTR5A	NM_024012.1	LAMA4	NM_002290
GAB4	NM_001037814	HUWE1	NM_031407	LAMB 3	NM_000228.1
GABPB2	NM_016654.2	IDH1	NM_005896.2	LAMB4	NM_007356
GABRA6	NM_000811.1	IGFBP3	NM_000598.2	LAMC1	NM_002293.2
GALGT2	NM_153446.1	IGSF22	NM_173588	LAS1L	NM_031206.2
GALNS	NM_000512.2	IGSF9	NM_020789.2	LCN10	NM_001001712
GDAP1L1	NM_024034.3	IK	NM_006083	LCN9	NM_001001676
GFI1	NM_005263	IL6ST	NM_002184.2	LDB1	NM_003893.3
GFI1B	NM_004188.2	IQSEC3	NM_015232	LDLRAD1	NM_001010978
GHRHR	NM_000823.1	IREM2	NM_181449.1	LEF1	NM_016269.2
GJA8	NM_005267	IRS2	NM_003749.2	LGR6	NM_021636.1
GLB1	NM_000404	IRS4	NM_003604.1	LIFR	NM_002310.2
GLI3	NM_000168.2	ISLR	NM_201526.1	LIG1	NM_000234.1
GLIPR1	NM_006851.1	ITGAE	NM_002208	LIG3	NM_013975.1
GMCL1L	NM_022471.2	ITGB3	NM_000212.2	LILRB1	NM_006669
GNAS	NM_000516.3	ITPR1	NM_002222	LMNB2	NM_032737.2
GNRH1	NM_000825	K6IRS3	NM_175068.2	LMO7	NM_005358.3
GPBP1	NM_022913	KCNA10	NM_005549.2	LOCI 22258	NM_145248.2
GPR112	NM_153834	KCNB2	NM_004770.2	LOC126147	NM_145807
GPR124	NM_032777.6	KCNC4	NM_004978.2	LOCI 29531	NM_138798.1
GPR158	NM_020752	KCND3	NM_004980.3	LOCI 57697	NM_207332.1
GPR50	NM_004224	KCNH4	NM_012285.1	LOC167127	NM_174914.2
GPR8	NM_005286.2	KCNQ5	NM_019842.2	LOC223075	NM_194300.1
GPR87	NM_023915.2	KCNT1	NM_020822	LOC388199	NM_001013638
GPX1	NM_000581	KCTD16	NM_020768	LOC91807	NM_182493.1
GRID1	NM_017551	KDR	NM_002253.1	LPIN1	NM_145693.1
GRID2	NM_001510.1	KIAA0182	NM_014615.1	LPPR2	NM_022737.1
GRIK1	NM_175611	KIAA0367	NM_015225	LRCH4	NM_002319
GRIK3	NM_000831.2	KIAA0415	NM_014855	LRP1	NM_002332.1
GRM1	NM_000838.2	KIAA0528	NM_014802	LRP2	NM_004525.1
GTF2B	NM_001514.2	KIAA0555	NM_014790.3	LRRC4	NM_022143.3
GUCY1A2	NM_000855.1	KIAA0556	NM_015202	LRRN6D	NM_001004432
HAPIP	NM_003947.1	KIAA0789	NM_014653	LRTM2	NM_001039029
HAPLN1	NM_001884.2	KIAA0934	NM_014974.1	LSP1	NM_001013253
HAT1	NM_003642.1	KIAA1078	NM_203459.1	LZTS2	NM_032429.1
HBXIP	NM_006402.2	KIAA1185	NM_020710.1	MAMDC1	NM_182830
HCAP-G	NM_022346.2	KIAA1285	NM_015694	MAN2A2	NM_006122
HDC	NM_002112.1	KIAA1409	NM_020818.1	MAP IB	NM_005909.2
HECTD1	NM_015382	KIAA1468	NM_020854.2	MAP2	NM_002374.2
HIC1	NM_006497	KIAA1529	NM_020893	MAP2K7	NM_145185
HIST1H1B	NM_005322.2	KIAA1727	NM_033393	MAPK8IP2	NM_012324
HIST1H1E	NM_005321.2	KIAA1875	NM_032529	MARLIN1	NM_144720.2
HIST1H2BM	NM_003521.2	KIAA2022	NM_001008537	MAST1	NM_014975
HIVEP1	NM_002114	KIF13A	NM_022113	MCF2L2	NM_015078.2
HIVEP3	NM_024503.1	KL	NM_004795.2	MCM3AP	NM_003906.3
HK3	NM_002115.1	KLF5	NM_001730.2	MCP	NM_172350.1
HOXC9	NM_006897.1	KLRF1	NM_016523	MCRS1	NM_006337.3
HPS3	NM_032383.3	KRAS	NM_004985.3	MED12L	NM_053002
HR	NM_005144.2	KRT20	NM_019010.1	MEF2C	NM_002397
HRH1	NM_000861.2	KRTAP10-2	NM_198693	MEGF6	NM_001409

140

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Gene Symbol

MET

MFN1

MGC13125

MGC15730

MGC16943

MGC20470

MGC26733

MGC29671

MGC32124

MGC33407

MGC33846

MGC39325

MGC39545

MGC48628

MGC52022

MGC52282

MGC5242

MGC8685

MKRN3

MLF2

MLL3

MMP11

MMP2

MMRN2

MN1

MPO

MPP3

MRGPRE

MRPL23

MS4A5

MTHFD1L

MUC1

MUC16

MYADML

MYO18B

MYO1B

MYOID

MYO5C

MYOHD1

MYR8

NALP7

NALP8

NAV3

NBEA

NCDN

NCR1

NDST3

NDUFA1

NEB

NELLI

NEUGRIN

NF1

NFATC1

Accession ID	Gene Symbol	Accession ID	Gene Symbol
NM_000245	NID	NM_002508.1	PDZD2
NM_033540.2	NLGN4X	NM_181332.1	PDZRN3
NM_032725.2	NODAL	NM_018055.3	PDZRN4
NM_032880.2	NOS3	NM_000603.2	PEBP4
NM_080663.1	NR3C2	NM_000901.1	PEG3
NM_145053	NTNG1	NM_014917	PERI
NM_144992	NUP210	NM_024923	PERQ1
NM_182538.3	NUP210L	NM_207308	PEX5L
NM_144611.2	OBSCN	NM_052843.1	PF6
NM_178525.2	ODZ1	NM_014253.1	PHIP
NM_175885	OLFM2	NM_058164.1	PHKB
NM_147189.1	OMA1	NM_145243.2	PIGO
NM_203452.1	OR10G3	NM_001005465	PIK3CA
NM_207491	OR13F1	NM_001004485	PIK3R5
NM_198563.1	OR1E2	NM_003554.1	PKHD1
NM_178453.2	OR2T33	NM_001004695	PKHD1L1
NM_024033.1	OR2T34	NM_001001821	PKNOX1
NM_178012.3	OR4A16	NM_001005274	PLA2G4B
NM_005664.1	OR4K14	NM_001004712	PLA2G4D
NM_005439.1	OR51E1	NM_152430	PLB1
NM_170606.1	OR51T1	NM_001004759	PLCG2
NM_005940.2	OR5H6	NM_001005479	PLEC1
NM_004530.1	OR5J2	NM_001005492	PLXND1
NM_024756.1	OR5K1	NM_001004736	PNLIPRP2
NM_002430	OR6C1	NM_001005182	PNMA3
NM_000250.1	OR6C6	NM_001005493	PNPLA1
NM_001932	OR6C75	NM_001005497	PPM1F
NM_001039165	OR8K3	NM_001005202	PPP1R12A
NM_021134	OSBP	NM_002556.2	PQBP1
NM_023945.2	OSBPL5	NM_020896	PQLC1
NM_015440.3	OSBPL5	NM_145638	PRDM9
NM_002456.3	OTOP2	NM_178160.1	PRF1
NM_024690	OVCH1	NM_183378	PRG2
NM_207329.1	OVGP1	NM_002557.2	PRIM A1
NM_032608	OXCT1	NM_000436.2	PRKCE
NM_012223.2	P2RX7	NM_002562.4	PRKCZ
NM_015194	P2RY14	NM_014879.2	PRKD1
NM_018728	PAK6	NM_020168.3	PRKDC
NM_001033579	PANK4	NM_018216.1	PRNPIP
NM_015011	PAOX	NM_207128.1	PRO0149
NM_139176.2	PARP8	NM_024615.2	PROL1
NM_176811.2	PBEF1	NM_005746.1	PROS1
NM_014903	PBX4	NM_025245.1	PRPS1
NM_015678	PBXIP1	NM_020524.2	PRSS1
NM_014284.1	PCDH11X	NM_032968.2	PRTG
NM_004829.3	PCDHA9	NM_014005	PSMA2
NM_004784.1	PCDHGA7	NM_032087	PSMC5
NM_004541.2	PCDHGB4	NM_032098	PTEN
NM_004543	PCP4	NM_006198	PTPRD
NM_006157.2	PCSK2	NM_002594.2	PTPRH
NM_016645.1	PDE11A	NM_016953	PTPRN2
NM_000267.1	PDGFD	NM_033135.2	PTPRS
NM_006162.3	PDILT	NM_174924.1	PTPRU

Accession

ID

NM_178140

NM_015009

NM_013377.2

NM_144962

NM_006210.1

NM_002616.1

NM_022574

NM_016559.1

NM_206996.1

NM_017934.4

NM_000293.1

NM_032634.2

NM_006218

NM_014308.1

NM_138694.2

NM_177531

NM_004571.3

NM_005090

NM_178034

NM_153021

NM_002661

NM_201378

NM_015103

NM_005396

NM_013364

NM_001039725

NM_014634.2

NM_002480

NM_005710.1

NM_025078.3

NM_020227

NM_005041.3

NM_002728.4

NM_178013.1

NM_005400.2

NM_002744.2

NM_002742.1

NM_006904

NM_024066

NM_014117.2

NM_021225

NM_000313.1

NM_002764.2

NM_002769.2

NM_173814

NM_002787.3

NM_002805.4

NM_000314

NM_130391.1

NM_002842

NM_002847.2

NM_130853.1

NM_005704.2

141

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Gene Symbol	Accession ID	Gene Symbol	Accession ID	Gene Symbol	Accession ID
PTPRZ1	NM_002851	SDCBP2	NM_080489.2	SUHW4	NM_001002843
PZP	NM_002864.1	SDK1	NM_152744	SYNE1	NM_182961.1
QKI	NM_006775.1	SEC24B	NM_006323	SYNPO	NM_007286.3
RAB38	NM_022337.1	SEC8L1	NM_021807.2	SYT9	NM_175733.2
RAB5C	NM_201434.1	SEMA3D	NM_152754	SYTL2	NM_206927
RABEP1	NM_004703	SERPINA3	NM_001085	T3JAM	NM_025228.1
RALGDS	NM_006266.2	SETBP1	NM_015559.1	TAF1L	NM_153809
RAPGEF4	NM_007023	SEZ6	NM_178860	TAF2	NM_003184
RARB	NM_000965.2	SF3A1	NM_005877.3	TAIP-2	NM_024969.2
RASAL2	NM_170692.1	SFMBT2	NM_001029880	TA-KRP	NM_032505.1
RASGRF2	NM_006909.1	SFRS6	NM_006275.4	TBC1D2B	NM_015079
RASGRP1	NM_005739	SGEF	NM_015595	TBX1	NM_005992.1
RASSF2	NM_170774.1	SH3TC1	NM_018986.2	TBX15	NM_152380
RASSF4	NM_032023.3	SHANK1	NM_016148.1	TBX22	NM_016954.2
RAVER2	NM_018211	SHQ1	NM_018130	TCEB3B	NM_016427.2
RB1CC1	NM_014781	SIGLEC7	NM_014385.1	TCERG1L	NM_174937.1
RBM10	NM_005676.3	SKIP	NM_030623	TCF3	NM_003200.1
RBP3	NM_002900.1	SKIV2L	NM_006929.3	TCF7L2	NM_030756.1
RCN1	NM_002901.1	SLB	NM_015662.1	TCFL5	NM_006602.2
RDH13	NM_138412	SLC11A2	NM_000617.1	TCOF1	NM_000356.1
RELN	NM_005045	SLC12A5	NM_020708.3	TFEC	NM_012252.1
RET	NM_020975.2	SLC12A7	NM_006598	TFG	NM_006070.3
REV3L	NM_002912.1	SLC1A7	NM_006671.3	TGFBR2	NM_003242.3
RFC4	NM_181573.1	SLC22A15	NM_018420	TGM2	NM_004613.2
RHEB	NM_005614.2	SLC22A9	NM_080866.2	TGM3	NM_003245
RHPN1	NM_052924	SLC26A10	NM_133489.1	THAP9	NM_024672.2
RIC3	NM_024557.2	SLC29A1	NM_004955.1	THR API	NM_005121
RIMBP2	NM_015347	SLC33A1	NM_004733.2	TIAM1	NM_003253.1
RIMS2	NM_014677	SLC37A4	NM_001467	TLR8	NM_138636.2
RNF182	NM_152737.1	SLC39A7	NM_006979	TLR9	NM_017442.2
RNF31	NM_017999	SLC4A9	NM_031467	TM7SF4	NM_030788.2
RNPEPL1	NM_018226.2	SLCO1A2	NM_134431.1	TMEM132B	NM_052907
ROBO1	NM_002941	SLCO1B3	NM_019844.1	TMEM16B	NM_020373
ROBO2	NM_002942	SLITRK4	NM_173078.2	TMPRSS4	NM_019894
RORA	NM_002943.2	SLITRK6	NM_032229	TNFRSF9	NM_001561.4
RPA3	NM_002947.2	SMAD2	NM_005901.2	TNN	NM_022093
RPAP1	NM_015540.2	SMAD3	NM_005902.2	TNNI3K	NM_015978.1
RPL6	NM_000970.2	SMAD4	NM_005359.3	TOP2A	NM_001067
RPS6KB1	NM_003161.1	SMTN	NM_006932.3	TP53	NM_000546.2
RREB1	NM_001003699	SNRPB2	NM_198220.1	TP53BP1	NM_005657.1
RTN4	NM_207521.1	SNTG2	NM_018968	TPX2	NM_012112.4
RUNX1T1	NM_175634.1	SNX5	NM_152227.1	TREX2	NM_080701
RYR2	NM_001035	SNX8	NM_013321.1	TRIM3	NM_033278.2
SACS	NM_014363.3	SOCS6	NM_004232.2	TRIM71	NM_001039111
SALL2	NM_005407	SORL1	NM_003105.3	TRMT5	NM_020810
SALL3	NM_171999.1	SPOCK3	NM_016950	TSKS	NM_021733.1
SCN10A	NM_006514	SPTBN2	NM_006946.1	TSN	NM_004622
SCN1A	NM_006920	ST8SIA4	NM_005668.3	TSP-NY	NM_032573.3
SCN3B	NM_018400.2	STAB1	NM_015136	TSPYL5	NM_033512
SCN7A	NM_002976	STAM	NM_003473.2	TTID	NM_006790.1
SCNN1B	NM_000336.1	STK32C	NM_173575.2	TTLL3	NM_015644.1
SCNN1G	NM_001039.2	STMN4	NM_030795.2	TTN	NM_133378
SDBCAG84	NM_015966.2	STX17	NM_017919.1	TTYH2	NM_032646

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Gene Symbol	Accession ID	Gene Symbol	Accession ID
TXLNB	NM_153235	ZNF624	NM_020787.1
TYSND1	NM_173555	ZNF659	NM_024697.1
UBE3C	NM_014671	ZNF714	NM_182515
UGDH	NM_003359.1	ZNHIT1	NM_006349.2
UHRF2	NM_152896.1	ZNRF4	NM_181710
UNC13B	NM_006377.2	ZSCAN5	NM_024303.1
UNC84B	NM_015374.1	ZZZ3	NM_015534.3
UNQ689	NM_212557.1
UQCRC2	NM_003366.1	Note: Gene symbols are standard
USP28	NM_020886	symbols assigned by Entrz Gene
USP32	NM_032582	(http://www. ncbi. nlm. nih. gov/sites/ent
USP52	NM_014871.2	rez?db=gene). Accession IDs
UTP14C	NM_021645	“NM_XXXX” are	uniquely assigned
UTX	NM_021140.1	to each gene by National Center for
VEST1	NM_052958.1	Biotechnology Information (NCBI) (http://www. ncbi. nlm. nih. gov/sites/ent
VIM	NM_003380.1	rez ?db=nuccore).
VPS13A	NM_033305.1
WAC	NM_016628.2
WDR19	NM_025132
WDR49	NM_178824.3
WNK1	NM_018979.1
WNT16	NM_016087.2
WNT8B	NM_003393.2
WRN	NM_000553.2
XKR3	NM_175878
XPO4	NM_022459
XRCC1	NM_006297.1
YEATS2	NM_018023
ZAN	NM_173059
ZBTB8	NM_144621.2
ZD52F10	NM_033317.2
ZDHHC7	NM_017740.1
ZFHX1B	NM_014795.2
ZFHX4	NM_024721
ZFPM2	NM_012082
ZNF155	NM_198089.1
ZNF217	NM_006526.2
ZNF232	NM_014519.2
ZNF235	NM_004234
ZNF262	NM_005095.2
ZNF291	NM_020843
ZNF43	NM_003423.1
ZNF435	NM_025231.1
ZNF442	NM_030824.1
ZNF471	NM_020813.1
ZNF480	NM_144684.1
ZNF521	NM_015461
ZNF536	NM_014717
ZNF540	NM_152606.2
ZNF560	NM_152476.1
ZNF568	NM_198539
ZNF572	NM_152412.1
ZNF582	NM_144690

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Claims (61)

1. We claim:

   1. A diagnostic method, wherein said method aids in the detection of a disease or other medical condition in a subject, the method comprising the steps of:

   (a) isolating a micro vesicle fraction from a biological sample from the subject;

   (b) detecting the presence or absence of a biomarker within the microvesicle fraction, wherein the biomarker is associated with the disease or other medical condition.
2. 2. A monitoring method, wherein said method aids in monitoring the status of a disease or other medical condition in a subject, the method comprising the steps of:

   (a) isolating a microvesicle fraction from a biological sample from the subject;

   (b) detecting the presence or absence of a biomarker within the microvesicle fraction, wherein the biomarker is associated with the disease or other medical condition.
3. 3. An evaluation method, wherein said method aids in evaluating treatment efficacy in a subject having a disease or other medical condition, the method comprising the steps of:

   (a) isolating a microvesicle fraction from a biological sample from the subject;

   (b) detecting the presence or absence of a biomarker within the microvesicle fraction, wherein the biomarker is associated with treatment efficacy for the disease or other medical condition.
4. 4. The method of any of claims 1-3, wherein the biological sample is a sample of bodily fluid.
5. 5. The method of any of claims 1-4, wherein the bio marker is:

   (i) a species of nucleic acid;

   (ii) the level of expression of a nucleic acid;

   (iii) a nucleic acid variant; or (iv) a combination thereof.
6. 6. The method of any of claims 1-5, wherein the biomarker is messenger RNA, microRNA, siRNA or shRNA.
7. 7. The method of any of claims 1-5, wherein the biomarker is DNA, single stranded DNA, complementary DNA, or noncoding DNA.

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8. 8. The method of any of claims 1-7, wherein the disease or other medical condition is a neoplastic disease or condition.
9. 9. The method of claim 8, wherein the biomarker is a nucleic acid listed in any of Tables 3-15, or a variant thereof.
10. 10. The method of claim 9, wherein the disease or other medical condition is glioblastoma.
11. 11. The method of claim 10, wherein the biomarker is a nucleic acid listed in any of Tables 8-12, or a variant thereof.
12. 12. The method of claim any of claims 8-11, wherein the biomarker is microRNA-21.
13. 13. The method of claim 8, wherein the biomarker is associated with a clinically distinct type or subtype of tumor.
14. 14. The method of any of claims 1-13, wherein the biomarker is a variant in the EGFR gene.
15. 15. The method of claim 14, wherein the biomarker is the EGFRvIII mutation.
16. 16. The method of claim 8, wherein the biomarker is associated with prostate cancer.
17. 17. The method of claim 16, wherein the biomarker is TMPRSS2-ERG, PCA-3, PSA, or variants thereof.
18. 18. The method of claim 8, wherein the biomarker is associated with melanoma.
19. 19. The method of claim 18, wherein the biomarker is a BRAF variant.
20. 20. The method of any of claims 1-3, wherein the biomarker is the expression level of one or more nucleic acids selected from the group consisting of let-7a; miR-15b; miR-16; miR-19b; miR-21; miR-26a; miR-27a; miR-92; miR-93; miR-320 and miR-20.
21. 21. The method of any of claims 1-7, wherein the disease or other medical condition is a metabolic disease or condition.
22. 22. The method of claim 21, wherein the metabolic disease or condition is diabetes, inflammation, or a perinatal condition.

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23. 23. The method of claim 21, wherein the metabolic disease or condition is associated with iron metabolism.
24. 24. The method of claim 21, wherein the biomarker is a nucleic acid encoding hepcidin, or a fragment or variant thereof.
25. 25. The method of any of claims 1-7, wherein the medical condition is a post transplantation condition.
26. 26. The method of any of claims 1-7, wherein the bio marker is mRNA encoding a member of the family of matrix metalloproteinases.
27. 27. The method of any of claims 1-7, wherein the bio marker is a nucleic acid listed in Table 10.
28. 28. The method of any of claims 1-7, wherein the disease or other medical condition is cancer and the biomarker is a nucleic acid variant of the Kras gene.
29. 29. The method of any of claims 1-28, wherein the microvesicles in the micro vesicle fraction have a diameter in the range of about 30 nm to about 800 nm.
30. 30. The method of claim 29, wherein the range is about 30 nm to about 200 nm.
31. 31. The method of any of claims 1-30, wherein step (a) is performed by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, affinity purification, microfluidic separation, or combinations thereof.
32. 32. The method of any of claims 1-31, wherein the biomarker is a nucleic acid and the method further comprises amplification of the nucleic acid.
33. 33. The method of any of claims 1-32, wherein the detecting step b) is performed by microarray analysis, PCR, hybridization with allele-specific probes, enzymatic mutation detection, ligation chain reaction (LCR), oligonucleotide ligation assay (OLA), flowcytometric heteroduplex analysis, chemical cleavage of mismatches, mass spectrometry, nucleic acid sequencing, single strand conformation polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE),

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34. 34. The method of any of claims 1-33, further comprising the isolation of a selective microvesicle fraction derived from cells of a specific type.
35. 35. The method of claim 34, wherein the cells are tumor cells.
36. 36. The method of claim 34, wherein the microvesicle fraction is derived from lung, pancreas, stomach, intestine, bladder, kidney, ovary, testis, skin, colorectal, breast, prostate, brain, esophagus, liver, placenta, fetus cells, or combinations thereof.
37. 37. The method of claim 34, wherein the selective micro vesicle fraction consists essentially of urinary microvesicles.
38. 38. A diagnostic method, wherein said method aids in the detection of a disease or other medical condition in a subject, the method comprising the steps of:

    (a) obtaining a biological sample from the subject; and (b) determining the concentration of microvesicles within the biological sample.
39. 39. A monitoring method, wherein said method aids in monitoring the status of a disease or other medical condition in a subject, the method comprising the steps of:

    (a) obtaining a biological sample from the subject; and (b) determining the concentration of microvesicles within the biological sample.
40. 40. The method of claim 38 or 39, further comprising the step of isolating a microvesicle fraction from the biological sample prior to determining the concentration.
41. 41. The method of claim 40, wherein the isolation step is performed by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, affinity purification, microfluidic separation, or combinations thereof.
42. 42. The method of claim 40 or 41, wherein the microvesicle fraction is derived from cells of a specific type.

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43. 43. The method of claim 42, wherein the cells are tumor cells.
44. 44. The method of claim 42, wherein the microvesicle fraction is derived from lung, pancreas, stomach, intestine, bladder, kidney, ovary, testis, skin, colorectal, breast, prostate, brain, esophagus, liver, placenta, fetus cells, or combinations thereof.
45. 45. The method of claim 42, wherein the selective micro vesicle fraction consists essentially of urinary microvesicles.
46. 46. The method of any of claims 38-45, wherein the microvesicles have a diameter in the range of about 30 nm to about 800 nm.
47. 47. The method of claim 46, wherein the range is about 30 nm to about 200 nm.
48. 48. A method for delivering a nucleic acid or protein to a target cell in an individual comprising, administering one or more microvesicles that contain the nucleic acid or protein, or one or more cells that produce such microvesicles, to the individual such that the microvesicles enter the target cell of the individual.
49. 49. The method of claim 48, wherein microvesicles are delivered to a brain cell.
50. 50. The method of claim 48 or 49, wherein the nucleic acid delivered is siRNA, shRNA, mRNA, microRNA, DNA, or combinations thereof.
51. 51. A method for performing a body fluid transfusion, comprising the steps of obtaining a fraction of donor body fluid free of all or substantially all microvesicles, or free of all or substantially all microvesicles from a particular cell type, and introducing the microvesicle-free fraction to a patient.
52. 52. The method of claim 51, wherein the cell type is a tumor cell type.
53. 53. The method of 51 or 52, wherein the body fluid is blood, serum or plasma.
54. 54. A composition of matter comprising a sample of body fluid free of all or substantially all microvesicles, or free of all or substantially all microvesicles from a particular cell type.
55. 55. The composition of claim 54, wherein the body fluid is blood, serum or plasma.

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56. 56. A method for performing body fluid transfusion, comprising the steps of obtaining a microvesicle-enriched fraction of donor body fluid and introducing the microvesicleenriched fraction to a patient.
57. 57. The method of claim 56, wherein the fraction is enriched with microvesicles derived from a particular cell type.
58. 58. The method of claim 56 or 57, wherein the body fluid is blood, serum or plasma
59. 59. A composition of matter comprising a sample of body fluid enriched with micro vesicles.
60. 60. The composition of claim 59, wherein the microvesicles are derived from a particular cell type.
61. 61. The composition of claim 59 or 60, wherein the bodily fluid is blood, serum or plasma.

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    FIG.1 a-e

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    0 8-1 9 7.00 7. ti t

    08-197 100 nm

    EXO'sinFix 17/7 HV=60.0kV

    Print Mag : 9350 0x(37.0in Direct Mag : 50 0 0 Ox

    10:43 08/29/08 Mi croscopi fft; KT.M

    FIG. 1 f

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    1^=0,04237

    RM, 04026

    1HXKH

    0.014——-ι¹.......i.....^.—>'^{1 1 1}—»——r-—i

    0.01 0.1 1 10 100 1000 10000

    0.01 0,1 1 10 100 1000 10000 Exosome A intensity

    Exosome B intensity d

    FIG. 2

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    Fig. 3a

    Fig. 3b

    1 2 3 4 5

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    Fig. 3c

    1 2

    HERV-K +DNase *—172bp

    Fig. 3d

    Tenascin-c +DNase

    197bp

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    Fig. 3f

    1 2 3 4

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    .....................j.........

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    ’tSsmpte 1

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    50™

    III I I I-1-ΓΊ-1 II I

    15 150 300 500 1500 [bp]

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    0.2

    FIG. 7

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    I Melanoma

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    Exosome profile

    0.5

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    FIG. 8

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    ι

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    B Normal control serum ϋ Glioma serum

    FIG. 10

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    Biopsy EGFR

    Serum micro vesicle GAPOH

    FIG. 11

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    Detection of BGFRvlH hi heahfty donors fern miocvmle BR

    I MW 31 32 33 34 35 36 3? 38 3S 4C 41 42 43 44 45 46 47 40 49 50 51 52 X. + X -

    FIG. 12

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    -ve control

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    FIG. 14a-d

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    Fig. 14e

    Fig. 14f

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    Fig. 14g +ve control Acftn -ve control Actin Actin DNase + Actin: DNase Fig. 14h

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    300 so

    T.MPRSS2:ER0

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    Stage prostate cancer biomarkers No. Grade Gleason PSA TMERG PCA-3 P1 T3NxM0 9 25 + + P2 T2cNxM0 7 24 + + P3 T2 6 7.4 - + P4 T2 6 3.6 - 4-

    FIG. 15

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    FIG. 16

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    0 hrs 15 hrs 24 hrs

    FIG. 17

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    300_ί cn c

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    EBM

    EBM+MV

    EGM

    Protein

    FIG. 18

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    P=0.0008

    MV

    FIG. 19

    2017272272 07 Dec 2017

    SEQUENCE LISTING

    <110> Massachussett General Hospital Skog, Johan <120> USE OF MICROVESICLES IN DIAGNOSIS AND PROGNOSIS OF MEDICAL DISEASES AND CONDISTIONS <130> 3635 <160> 58 <170> PatentIn version 3.5 <210> 1 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 1 cgaccacttt gtcaagctca 20 <210> 2 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 2 ggtggtccag gggtcttact 20 <210> 3 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 3 gagagcctcc cacagttgag 20 <210> 4 <211> 20 <212> DNA

    2017272272 07 Dec 2017 <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 4 tttgccagaa tctcccaatc 20 <210> 5 <211> 17 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 5 ccatgctcat sgattgg 17 <210> 6 <211> 19 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 6 attctrttcc attggtcta 19 <210> 7 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 7 gccccttctg gaaaacctaa 20 <210> 8 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers

    2017272272 07 Dec 2017 <400> 8 agccaatgcc agttatgagg 20 <210> 9 <211> 19 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 9 gaaggtgaag gtcggagtc 19 <210> 10 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 10 gaagatggtg atgggatttc 20 <210> 11 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 11 ccagtattga tcgggagagc 20 <210> 12 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 12 ccagtattga tcgggagagc 20 <210> 13

    2017272272 07 Dec 2017 <211> 18 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 13 atgcgaccct ccgggacg 18 <210> 14 <211> 18 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 14 gagtatgtgt gaaggagt 18 <210> 15 <211> 25 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 15 ggctctggag gaaaagaaag gtaat 25 <210> 16 <211> 21 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 16 tcctccatct catagctgtc g 21 <210> 17 <211> 20 <212> DNA <213> Artificial sequence <220>

    2017272272 07 Dec 2017

    <223> synthetic DNA sequence used as primers <400> 17 attaaccctg ctcggtcctt 20 <210> 18 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 18 accctggagt tgatgtcgtc 20 <210> 19 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 19 cgtcactggc aaatttgatg 20 <210> 20 <211> 18 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 20 agtgcagctc caccgact 18 <210> 21 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 21 gcacataccc aaacaacacg 20

    <210> 22 <211> 20 <212> DNA <213> Artificial sequence <220>

    2017272272 07 Dec 2017

    <223> synthetic DNA sequence used as primers <400> 22 tcccaagtta atcggaatgc 20 <210> 23 <211> 22 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 23 caaaatggaa tctcttcaaa cg 22 <210> 24 <211> 21 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 24 aacaagattt gcggtgtctt t 21 <210> 25 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 25 gtggccaaga ctgtgaggat 20 <210> 26 <211> 20 <212> DNA <213> Artificial sequence

    2017272272 07 Dec 2017 <220>

    <223> synthetic DNA sequence used as primers <400> 26 ggtggtgcag gactcatctt 20 <210> 27 <211> 24 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 27 gaattgacaa ccctgtgttt tctc 24 <210> 28 <211> 18 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 28 tgcctgcagg aaggagtc 18 <210> 29 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 29 caggccatga aggcagtagt 20 <210> 30 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 30

    2017272272 07 Dec 2017 cgggaataga actcgtcgat 20 <210> 31 <211> 20 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 31 tccctgggca cttgtatgat 20 <210> 32 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 32 agctcgaagg gcagagaatc 20 <210> 33 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 33 cttcagcact cactggctgt 20 <210> 34 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 34 gcttccctga gttctgttgc 20

    <210> 35 <211> 20

    2017272272 07 Dec 2017 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 35 ccacccactc taaagcttcg 20 <210> 36 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 36 gatcttggtt cgccatctgt 20 <210> 37 <211> 21 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 37 tcacacacaa cttcagcaac c 21 <210> 38 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 38 ggccaggatg aagtcgtaga 20 <210> 39 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers 9

    2017272272 07 Dec 2017 <400> 39 acaccggctg ctctatgaat 20 <210> 40 <211> 18 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 40 aggggtccga tccagaag 18 <210> 41 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 41 cagctctcca tcctctggac 20 <210> 42 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 42 ccgtgcataa tcagcatgaa 20 <210> 43 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 43 aaactggaac ggtgaaggtg 20

    <210> 44 <211> 18 <212> DNA <213> Artificial sequence <220>

    2017272272 07 Dec 2017

    <223> synthetic DNA sequence used as primers <400> 44 ggcacgaagg ctcatcat 18 <210> 45 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 45 gaagtccctt gccatcctaa <210> 46 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers 20 <400> 46 gctatcacct cccctgtgtg <210> 47 <211> 21 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers 20 <400> 47 taggcgcgag ctaagcagga g <210> 48 <211> 19 <212> DNA <213> Artificial sequence 21

    2017272272 07 Dec 2017 <220>

    <223> synthetic DNA sequence used as primers <400> 48 gggggttgag acagccatc <210> 49 <211> 19 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 49 cgcgagctaa gcaggaggc 19 <210> 50 <211> 25 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400>

    <400> 50 gtaggcacac tcaaacaacg actgg <210> 51 <211> 16 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 51 agtccgctgt gagtct 16 <210> 52 <211> 20 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 52 ccacacatct gctgaaatgg <400>

    <210> 53 <211> 20 <212> DNA <213> Artificial sequence <220>

    2017272272 07 Dec 2017

    <223> synthetic DNA sequence used as primers <400> 53 atcgacggca ctttctgagt 20 <210> 54 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 54 tgtgtggcct cagatggtaa 20 <210> 55 <211> 24 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 55 ttcatgaaga cctcacagta aaaa 24 <210> 56 <211> 20 <212> DNA <213> Artificial sequence <220> <223> synthetic DNA sequence used as primers <400> 56 tctggtgcca tccacaaaat 20 <210> 57 <211> 20 <212> DNA

    2017272272 07 Dec 2017 <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 57 cgcagcagaa aatgcagatg 20 <210> 58 <211> 20 <212> DNA <213> Artificial sequence <220>

    <223> synthetic DNA sequence used as primers <400> 58 cacaacagac gggacaactt 20