KR20210113140A - Composition And Kit For Diagnosing Prognosis Of Kidney Cancer According To Tumor Type - Google Patents

Abstract

The present invention provides a composition for diagnosing the prognosis of renal cancer depending on the type of tumor a patient has, a kit for diagnosing the prognosis of renal cancer, and a method for providing the information necessary for diagnosing the prognosis of renal cancer using the same. The composition and the kit for diagnosing the prognosis of renal cancer according to the present invention enable users to diagnose and predict the prognosis of renal cancer, such as the survival rate and recurrence rate after treatment, depending on the type of tumor a patient has, thereby helping them to establish a treatment strategy for a renal cancer patient.

Description

Composition And Kit For Diagnosing Prognosis Of Kidney Cancer According To Tumor Type

The present invention relates to a composition for prognostic diagnosis of renal cancer according to tumor type, a kit for prognostic diagnosis of renal cancer, and a method for providing information necessary for prognostic diagnosis of a renal cancer patient using the same.

The kidney is an important urinary organ having a role of excreting wastes in the living body to the outside of the body by filtering blood and producing urine. At the same time, it is also an important endocrine organ that produces hormones such as angiotensin, which regulates blood pressure, and erythropoietin, a red blood cell hematopoietic factor.

Tumors that occur in the kidney include renal cell carcinoma (RCC) that occurs in adults, Wilms' tumor that occurs in children, and sarcoma as a rare tumor. Kidney cancer refers to renal cell carcinoma that occurs mostly in the parenchyma of the kidney (the part of the kidney that makes urine, which is composed of the medulla and the cortex). Although genetic factors are also known as risk factors for kidney cancer, in general, smoking and excessive fat intake are included. In addition, it is known that the incidence of tumors is high in patients receiving dialysis for a long time.

Renal cell carcinoma includes clear cell RCC, papillary RCC, chromophobe RCC, medullary RCC, and unclassifiable renal cell carcinoma. (unclassified RCC), and among them, papillary renal cell carcinoma is the second most common type, accounting for about 15-20% of all renal cell carcinomas.

Kidney cancer has almost no symptoms when the size of the tumor is small, and symptoms appear only when the tumor grows to a certain extent and pushes the organs away. Therefore, the diagnosis is often delayed, and when first diagnosed, about 30% of patients appear to have already metastasized. The most common symptom is hematuria, but this also occurs in only 60% of patients. Rather, symptoms such as shortness of breath, cough, and headache appear depending on the metastasized site, and the diagnosis of kidney cancer due to these metastases is up to 30% of all patients. Because kidney cancer can cause high blood pressure, hypercalcemia, and liver function abnormalities due to certain hormones produced by cancer cells, tumors are sometimes discovered while examining these other symptoms. Recently, it is often discovered incidentally on an imaging test while undergoing a medical examination without any symptoms.

Kidney cancer has a high survival rate due to tumor removal after onset, but it is difficult to diagnose at an early stage because there are no clear symptoms. For this reason, early diagnosis of kidney cancer and development of markers that can check the remaining lifespan after cancer onset is necessary.

Patent Document 1 discloses transglutaminase 2 as a marker used for detection or diagnosis of human kidney cancer. Although markers for diagnosing cancer, including kidney cancer, have been developed, there has been no study yet on the relationship between a marker that can measure the prognosis of a kidney cancer patient, particularly the tumor type of kidney cancer and a mutation in a specific gene. am.

The present inventors have focused on the need to develop a marker capable of diagnosing the prognosis of renal cancer patients in order to diagnose renal cancer or to discover therapeutic agents for renal cancer patients to determine treatment strategies. The relationship between genetic mutations and tumor type of kidney cancer was studied.

Korean Patent Publication No. 1267580

In order to apply a therapeutic strategy suitable for renal cancer patients, it is necessary to develop a marker that can predict the prognosis of renal cancer patients and provide information to determine a treatment strategy. An object of the present invention is to provide a marker that helps in prognostic diagnosis of renal cancer patients and determination of treatment strategies for renal cancer patients based on the tumor type of renal cancer.

One aspect of the present invention provides a composition for prognostic diagnosis of renal cancer comprising a reagent capable of detecting a tumor type-specific marker of renal cancer including a mutation in the SSC5D gene.

Another aspect of the present invention provides a kit for prognostic diagnosis of renal cancer comprising a reagent capable of detecting a tumor type-specific marker of renal cancer containing a mutation in the SSC5D gene.

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a renal cancer patient; Checking the presence or absence of a tumor type-specific marker using the composition for prognostic diagnosis of kidney cancer or the kit for prognostic diagnosis of kidney cancer with respect to the sample DNA; providing information necessary for prognostic diagnosis of renal cancer patients including; provides a way to

Using the composition for prognostic diagnosis of renal cancer of the present invention and a kit for prognostic diagnosis of renal cancer comprising the same, prognosis such as viability or recurrence after treatment can be diagnosed and predicted according to the tumor type of renal cancer. This can help establish a treatment strategy for kidney cancer patients.

1 shows the total survival rate of a kidney cancer patient with a mutation in the corresponding gene (red) and a kidney cancer patient without a mutation in the corresponding gene (blue) with respect to three genes of the first group of candidate genes associated with tumor type. and a graph of disease-free survival.
2 shows the total survival rate and disease-free survival rate of a kidney cancer patient with a mutation in the corresponding gene (red) and a kidney cancer patient without a mutation in the corresponding gene (blue) with respect to the SSC5D gene of the second group of candidate genes correlated with the survival rate. shows the graph of
3 is a graph of the total survival rate and disease-free survival rate of a kidney cancer patient with a mutation in the gene (red) and a kidney cancer patient without a mutation in the gene (blue) for a total of 52 genes related to the tumor type. indicates.

In this specification, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the experimental methods described below are those well known and commonly used in the art.

In the present invention, the term 'gene' and its variants include DNA fragments involved in polypeptide chain generation; It includes regions before and after the coding region, eg promoters and 3'-untranslated regions, respectively, as well as intervening sequences (introns) between individual coding fragments (exons).

As used herein, the term 'cancer' includes any member of a class of diseases characterized by the uncontrolled growth of abnormal cells. The term includes all known cancers and neoplastic conditions, whether characterized as malignant, benign, soft tissue or solid, and cancers of all stages and grades, including cancers before and after metastasis.

In the present invention, the term 'prognosis' refers to the progress and cure of neoplastic diseases such as cancer, such as the possibility of cancer-caused death or progression, including recurrence, metastatic spread, and drug resistance, for example. For the purpose of the present invention, it may be to predict the prognosis of kidney cancer, preferably to predict the disease-free survival rate or survival rate of renal cancer patients.

In the present invention, the term 'diagnosis' refers to confirming the presence or characteristics of a pathological condition, and for the purpose of the present invention, not only confirming whether or not cancer occurs, but also recurrence, metastasis, drug reactivity, resistance of the subject after treatment of cancer It means judging whether or not Preferably, when using the mutation of the gene of the present invention, it is possible to predict whether or not the subject will develop cancer, as well as whether the prognosis of the subject will be good in the future by checking whether the mutation is present from the subject's sample.

In the present invention, the term 'tumor type-specific marker' may refer to a mutation of a gene or mutations in a gene that can be an index predicting the prognosis of renal cancer in a subject after treatment of a renal cancer patient according to a tumor type. Also, in the present invention, the 'marker gene' may be used to refer to each gene mutation included in the tumor type-specific marker.

1. Composition and kit for prognostic diagnosis of kidney cancer

One aspect of the present invention provides a composition for prognostic diagnosis of renal cancer comprising a reagent capable of detecting a tumor type-specific marker of renal cancer. The tumor type-specific marker of the composition for prognostic diagnosis of renal cancer of the present invention may be an index predicting the prognosis of renal cancer in a subject after treatment according to the tumor type of renal cancer.

For example, when the tumor type-specific marker is identified, it may be determined that the survival rate of the subject is lower or the recurrence rate is higher than that of a person for which the tumor type-specific marker is not identified.

Specifically, the tumor type-specific marker may include a mutation in the SSC5D gene (Gene bank accession number: NM_001144950.2). In addition, the tumor type-specific marker is a mutation of the DDX20 gene (Gene bank accession number: NM_007204.5), a mutation of the FLG gene (Gene bank accession number: NM_002016.1) and the KYAT3 gene (Gene bank accession number: NM_001008661.3) ) may further comprise at least one selected from the group consisting of mutations.

The full names of the abbreviations of the genes may be SSC5D (scavenger receptor cysteine rich family member with 5 domains), DDX20 (DEAD-box helicase 20), FLG (filagrin) and KYAT3 (kynurenine aminotransferase 3), respectively.

In the present invention, the reagent capable of detecting the survival-specific marker may include one or more selected from the group consisting of a primer, a probe, an antibody, and an aptamer for the survival-specific marker. The primer, probe, antibody or aptamer can be manufactured using a known technique, and a primer, probe, antibody or aptamer capable of detecting a mutation of a gene of the present invention is included in the scope of the present invention.

In the present invention, the term 'primer' is a nucleic acid sequence having a short free 3' hydroxyl group, which can form a base pair with a complementary template and is a starting point for template strand copying. It refers to a short nucleic acid sequence that functions as The primers are capable of initiating DNA synthesis in the presence of reagents for the polymerization reaction (ie, DNA polymerase or reverse transcriptase) and the four different nucleoside triphosphates in appropriate buffer solutions and temperatures. In the present invention, PCR amplification is performed using the forward and reverse primers of the mutant gene to determine the presence or absence of a corresponding gene marker through the generation of a desired product, and it can be used for diagnosis. For example, in the case of a forward primer, a primer corresponding to a mutant in which deletion, substitution, or insertion has occurred is designed, and a reverse primer is designed and PCR corresponding to a position where mutation does not occur, mutation of the gene of the present invention In the case of a chain, an amplification product will be generated by PCR, but if it is not a mutant of the gene of the present invention, no amplification product will be generated. PCR conditions, forward and reverse primer lengths can be modified based on those known in the art.

In the present invention, the term 'probe' refers to a nucleic acid fragment such as RNA or DNA capable of forming a specific binding with DNA, and consists of several bases to several hundred bases as long as possible. Since the probe is labeled, the presence or absence of a specific DNA can be confirmed. The probe may be manufactured in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, an RNA probe, or the like. In the present invention, by performing hybridization using a probe complementary to a mutation of a gene, it is possible to diagnose whether kidney cancer recurs based on whether or not hybridization occurs. For example, when a probe corresponding to a mutant having a deletion, substitution or insertion is synthesized and the probe is hybridized with the genomic DNA of a kidney cancer patient, hybridization will occur in the case of a mutant of the gene of the present invention, but the present invention If it is not a mutant of the gene, hybridization will not occur. Selection of suitable probes and hybridization conditions can be modified based on those known in the art.

In the present invention, the term 'antibody' is a term known in the art and refers to a specific protein molecule directed against an antigenic site. In the present invention, the antibody may refer to an antibody that specifically binds to each marker gene. Such an antibody can be prepared by cloning each marker gene into an expression vector according to a conventional method to obtain a protein encoded by the marker gene, and from the obtained protein by a conventional method. This also includes a partial peptide that can be made from the protein, and the partial peptide of the present invention contains at least 7 amino acids, preferably 9 amino acids, more preferably 12 or more amino acids. The form of the antibody of the present invention is not particularly limited, and a part thereof is included in the antibody of the present invention as long as it has polyclonal antibody, monoclonal antibody, or antigen-binding property, and all immunoglobulin antibodies are included. Furthermore, the antibody of the present invention includes a special antibody such as a humanized antibody. Antibodies used for the detection of marker genes of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule refers to a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab') ₂ and Fv.

As used herein, the term 'aptamer' refers to a single-stranded nucleic acid (DNA, RNA, or modified nucleic acid) that has a stable tertiary structure by itself and can bind to a target molecule with high affinity and specificity. Aptamers can be synthesized by known chemical methods, for example, by a method called SELEX (Systematic Evolution of Ligands of Exponential enrichment) for various target substances (proteins, sugars, dyes, DNA, metal ions, cells, etc.) You can develop aptamers.

The mutation of the gene may include any one or more mutations, for example, a truncating mutation, a missense mutation (or a missense mutation), a nonsense mutation, a frame shift. ) mutation, in-frame mutation (or in-frame mutation), splice mutation, and splice_region mutation may have at least one mutation selected from the group consisting of mutations. The frameshift mutation may be at least one of a frame shift insert (FS ins) mutation and a frame shift delete mutation (FS del). The in-frame mutation may be at least one of an in-frame insertion (IF ins) mutation and an in-frame delete (IF del) mutation.

The term "X#Y" with respect to a mutation in a polypeptide sequence is self-recognized in the art, where "#" indicates the mutation site with respect to the amino acid number of the polypeptide, and "X" is that of the wild-type amino acid sequence. indicates the amino acid found at that position, and "Y" indicates the mutant amino acid at that position. For example, the designation “S1077R” with respect to a SSC5D polypeptide indicates that a serine is present at amino acid number 1077 of the wild-type SSC5D sequence and that serine has been replaced by arginine in the mutant SSC5D sequence. Mutations in these genes are as follows:

The mutation of the SSC5D gene may be a frameshift deletion mutation of W801Gfs*22 or a missense mutation of S1077R in the amino acid sequence of SEQ ID NO: 1. The notation method for frameshift mutations is amino acid type (amino acid position) amino acid type fs* (number of nucleotides from the amino acid position to the stop codon in the downstream direction) explanation is omitted).

The mutation of the DDX20 gene may be a missense mutation of L126F, a missense mutation of T113S, a missense mutation of F315C or a missense mutation of E709K in the amino acid sequence of SEQ ID NO: 2.

The mutation of the FLG gene may be a missense mutation that is H822N, a nonsense mutation that is G2564*, a missense mutation that is R3780T, a missense mutation that is E3429D, or a missense mutation that is S2029C in the amino acid sequence of SEQ ID NO:3. In the nonsense mutation, * indicates that the amino acid synthesis at the corresponding amino acid position is terminated (the description is omitted below).

The mutation of the KYAT3 gene may be a missense mutation of T309K, a nonsense mutation of K399*, a frameshift deletion mutation of K399Nfs*3, or a frameshift deletion mutation of K399Mfs*4 in the amino acid sequence of SEQ ID NO:4.

Next generation sequencing (NGS), RT-PCR, direct nucleic acid sequencing method, and microarray can be used as an analysis method for diagnosing the prognosis of kidney cancer using the mutation of the gene. Any method that can confirm the existence of a mutation using a mutation of a gene can be applied without limitation. In one embodiment, the presence of a mutation is determined using an anti-(mutant of each gene) antibody or nucleic acid probe that hybridizes under stringent conditions to the polynucleotide of the mutant of each gene. In another embodiment, the antibody or nucleic acid probe is detectably labeled. In another embodiment, the label is selected from the group consisting of an immunofluorescent label, a chemiluminescent label, a phosphorescent label, an enzymatic label, a radioactive label, avidin/biotin, colloidal gold particles, colored particles, and magnetic particles. In another embodiment, the presence of the mutation is determined by radioimmunoassay, western blot assay, immunofluorescence assay, enzymatic immunoassay, immunoprecipitation assay, chemiluminescence assay, immunohistochemical assay, dot blot assay, slot blot assay or flow cytometry. determined by the assay. In another embodiment, the presence of the mutation is determined by RT-PCR. In another embodiment, the presence of a mutation is determined by nucleic acid sequencing.

As used herein, the term 'polynucleotide' generally refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. Thus, for example, polynucleotides as defined herein include, but are not limited to, single- and double-stranded DNA, DNA comprising single- and double-stranded regions, single- and double-stranded RNA, and single- and double-stranded DNA. - RNA comprising a region, single-stranded or more typically double-stranded, or hybrid molecule comprising DNA and RNA, which may comprise single- and double-stranded regions. Thus, DNA or RNA having a backbone that has been modified for stability or other reasons is a 'polynucleotide' as the term is intended herein. Also included in the term 'polynucleotide' as defined herein is DNA or RNA comprising an unconventional base such as inosine or a modified base such as a tritiated base. In general, the term 'polynucleotide' includes all chemically, enzymatically and/or metabolically modified forms of unmodified polynucleotides. Polynucleotides can be prepared by a variety of methods, including in vitro recombinant DNA-mediated techniques, and by expression of DNA in cells and organisms.

Another aspect of the present invention provides a kit for prognostic diagnosis of renal cancer comprising a reagent capable of detecting a tumor type-specific marker of renal cancer containing a mutation in the SSC5D gene.

The tumor type-specific marker may further include at least one selected from the group consisting of a mutation of the DDX20 gene, a mutation of the FLG gene, and a mutation of the KYAT3 gene.

For example, when at least one of the survival-specific markers is detected, the individual may determine that the survival rate is lower than that of a person for which the survival-specific marker is not identified, or it may be determined that the recurrence rate is high.

The reagent capable of detecting the survival-specific marker may include one or more selected from the group consisting of a primer, a probe, an antibody, and an aptamer, and the specific details are the same as described above, and thus a detailed description thereof will be omitted.

The kit of the present invention may be an RT-PCR kit, a DNA chip kit or a protein chip kit. As an example, the RT-PCR kit for measuring the mRNA expression level of the marker gene of the present invention may be a kit including essential elements necessary for performing RT-PCR. The RT-PCR kit contains, in addition to each primer pair specific for the marker gene, a test tube or other suitable container, reaction buffer (with varying pH and magnesium concentration), deoxynucleotides (dNTPs), Taq-polymerase and enzymes such as reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterile water, and the like. In addition, a pair of primers specific to a gene used as a quantitative control may be included.

As another example, the DNA chip kit of the present invention may include essential elements necessary for performing a DNA chip analysis method. The DNA chip kit may include a substrate to which cDNA corresponding to a marker gene or a fragment thereof is attached as a probe, and reagents, agents, enzymes, and the like for producing a fluorescently labeled probe. In addition, the substrate may include cDNA corresponding to a quantitative control gene or a fragment thereof.

As another example, the kit of the present invention is a protein chip kit for measuring the level of a protein expressed from the marker gene, and the kit is not particularly limited thereto, but includes a substrate, an appropriate buffer, It may include a chromogenic enzyme or a secondary antibody labeled with a fluorescent substance, a chromogenic substrate, and the like. The substrate is not particularly limited thereto, but a nitrocellulose membrane, a 96-well plate synthesized from a polyvinyl resin, a 96-well plate synthesized from a polystyrene resin, a glass slide glass, etc. may be used, and the chromogenic enzyme is not particularly limited thereto. However, peroxidase and alkaline phosphatase may be used, and the fluorescent material may be FITC, RITC, etc., but is not particularly limited thereto, and the color development substrate solution is not particularly limited thereto, but ABTS (2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) or OPD (o-phenylenediamine), TMB (tetramethyl benzidine).

In addition, the kit of the present invention may further include a buffer, an indicator, or a combination thereof as a reagent.

The kit for prognostic diagnosis of kidney cancer of the present invention is very economical because it saves time and money compared to the existing general gene mutation detection method. Using existing gene mutation detection methods such as Single Strand Conformational Polymorphism (SSCP), Protein Truncation Test (PTT), cloning, and direct sequencing, it takes several days on average to test all one gene. It takes several months. In addition, gene mutations can be precisely tested quickly and simply through next generation sequencing (NGS). When mutations are tested by conventional analysis methods such as SSCP, cloning, direct sequencing, and Restriction Fragment Length Polymorphism (RFLP), it takes about a month to complete the test, whereas using the kit of the present invention, sample DNA is prepared If it is done, results can be obtained within about 10 to 11 hours, and since a primer set capable of detecting mutations is integrated on one chip, not only time but also cost can be reduced compared to the conventional method. Compared to the conventional method, the average cost of reagents is less than half per experiment, so even greater cost savings can be expected when the researcher's labor costs are taken into account.

2. A method of providing information necessary for prognostic diagnosis of kidney cancer

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a renal cancer patient; Checking the presence or absence of a tumor type-specific marker using the composition for prognostic diagnosis of kidney cancer or the kit for prognostic diagnosis of kidney cancer with respect to the sample DNA; providing information necessary for prognostic diagnosis of renal cancer patients including; provides a way to

The description of the ' composition and kit for prognostic diagnosis of kidney cancer' is the same as that described in '1. Composition and kit for prognostic diagnosis of kidney cancer ', and thus a detailed description thereof will be omitted.

The term 'patient' usually includes humans as well as other animals, such as other primates, rodents, dogs, cats, horses, sheep, pigs, and the like.

The term 'sample' refers to a sample of an individual or tissue in which cancer or tumor has already occurred or is expected to occur, and a target sample to diagnose its prognosis. Specifically, it may refer to a tumor lysate or extract prepared from frozen tissue obtained from a patient with renal cancer.

The term 'subject' includes a subject diagnosed with or suspected of having kidney cancer.

The method can predict the overall survival or disease-free survival of renal cancer patients.

As used herein, the term 'overall survival (OS)' includes a clinical endpoint describing a patient who is alive for a finite time after being diagnosed with or treated for a disease, such as cancer, regardless of whether the cancer recurs or not. means the possibility of surviving.

In the present invention, the term 'disease-free survival (DFS)' includes a period in which a patient survives without cancer recurrence after treatment for a specific disease (eg, cancer).

According to the present invention, by confirming the presence of a mutation in the gene of the present invention in a sample of a kidney cancer patient, it is possible to predict what prognosis an individual having the target sample has for cancer. This method can also be achieved by comparing the total survival or disease-free survival of subjects in a control group that does not have a mutation known to have a good prognosis. In the present invention, an individual known to have a good prognosis means an individual with no history of metastasis, recurrence, death, etc. after cancer has developed.

The tumor type-specific marker may include a mutation in the SSC5D gene.

In addition, the tumor type-specific marker may further include at least one selected from the group consisting of a mutation of the DDX20 gene, a mutation of the FLG gene, and a mutation of the KYAT3 gene.

The method of providing information necessary for prognostic diagnosis of the renal cancer patient may predict the total survival rate or disease-free survival rate of the renal cancer patient. For example, the method may include, when the tumor type-specific marker is identified, determining that the survival rate is lower than that of a person for which the tumor type-specific marker is not identified. Or vice versa.

In addition, the method may include; when the tumor type-specific marker is identified, determining that the recurrence rate of kidney cancer is higher than that of a person for which the tumor type-specific marker is not identified. Or vice versa.

As such, it has not yet been revealed that the prognosis, such as the viability or recurrence possibility of kidney cancer, can be diagnosed according to the tumor type of kidney cancer by using the mutation of the SSC5D gene, which is a mutation of the gene of the present invention. In addition, it has not been reported that the total survival rate or disease-free survival rate may be different for each gene. The present inventors have identified for the first time that mutations of the above genes can be used as diagnostic markers for predicting the difference in therapeutic effect depending on the tumor type of kidney cancer or for diagnosing the prognosis of a kidney cancer patient.

The method for providing information necessary for predicting the difference in the therapeutic effect of renal cancer patients of the present invention can be used to diagnose a gene mutation in kidney cancer, increase the survival rate of kidney cancer patients, or lower the recurrence rate. Through the method for prognostic diagnosis of kidney cancer of the present invention, it is possible to predict the therapeutic effect according to the tumor type of kidney cancer, or to predict the survival rate or recurrence rate of kidney cancer patients, using information on the occurrence of mutations in the kidney cancer gene. It can provide information on the selection of a treatment as well as the discovery of a suitable treatment for the patient, so that it is possible to efficiently design a therapeutic strategy for kidney cancer.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

However, the following examples and experimental examples are only for illustrating the present invention, and the content of the present invention is not limited by the following examples and experimental examples.

Example

Securing genetic and clinical information

In order to derive tumor type-specific markers that can diagnose the prognosis of renal cancer patients, relapse, metastasis, death, Data on observation time and the like were obtained and used for analysis.

number of patients ratio(%) tumor type type 1 85 52.5 type 2 77 47.5 Sum 162 100

Selection of markers related to tumor type

As shown in Table 1 above, for 162 data that can confirm the tumor type, according to the tumor type, it is divided into two groups: Type 2 (T0) / Type 1 (T1), and 3 Feature Selection (Information Gain, Chi- Square, MR) method was applied to machine learning, and the following 52 genes related to tumor type were derived:

ANKRD13D, ANTXR2, ARHGEF3, AXIN1, C19orf57, C8A, CAMK2B, KYAT3, CCDC178, CD109, CDAN1, CMBL, CTDSPL, DDX20, DNAJB6, DNAJB9, DOCK4, DPP10, DROSHA, EYEP3, FAM161B, FLG3, FAM1614 IL17RC, KIAA1244, KIDINS220, KIF5A, LPIN1, MAPK6, MDN1, MFSD10, MSTN, MYBBP1A, NCOA1, NCOA2, NPY2R, PUM1, R3HDM2, RGSL1, VLC17A8, SLC22A23, WDWC, TM8, WDRSC5, WDWC, TM8 ZC3H13, ZER1.

The p-value of the analysis result is shown in Table 2 below, and for convenience in data interpretation, overall survival and disease-free survival according to the Kaplan Meier survival assay performed in Example 2 to be described later. ) and the p value.

number of mutations mutation
(%) Cyto band Mutation type tumor type Fisher test (p-value)
Total survival (p-value) Disease-free survival (p-value) T1 T2 T1 ratio
(%) cut missense in-frame ANKRD13D 3 One 11q13.2 0 3 0 3 0 100 0.101 0.57 0.49 ANTXR2 2 0.7 4q21.21 2 0 0 2 0 100 0.219 0.657 0.565 ARHGEF3 3 One 3p14.3 0 3 0 3 0 100 0.101 0.609 0.497 AXIN1 3 One 16p13.3 0 3 0 3 0 100 0.101 0.616 0.494 C19orf57 3 One 19p13.12 2 One 0 3 0 100 0.101 0.694 0.599 C8A 2 0.7 1p32.2 0 2 0 2 0 100 0.219 0.387 0.383 CAMK2B 2 0.7 7p13 0 2 0 2 0 100 0.219 0.362 0.701 KYAT3 4 1.4 NA 3 One 0 4 0 100 0.046 0.706 0.61 CCDC178 2 0.7 18q12.1 0 2 0 2 0 100 0.219 0.657 0.561 CD109 2 0.7 6q13 One One 0 2 0 100 0.219 0.62 0.516 CDAN1 3 One 15q15.2 0 3 0 3 0 100 0.101 0.394 0.344 CMBL 3 One 5p15.2 One One One 3 0 100 0.101 0.548 0.518 CTDSPL 2 0.7 3p22.2 One One 0 2 0 100 0.219 0.467 0.452 DDX20 4 1.4 1p13.2 0 4 0 4 0 100 0.046 0.362 0.336 DNAJB6 2 0.7 7q36.3 0 2 0 2 0 100 0.219 0.455 0.441 DNAJB9 2 0.7 7q31.1|14q24.2-q24.3 2 0 0 2 0 100 0.219 0.499 0.585 DOCK4 3 One 7q31.1 0 3 0 3 0 100 0.101 0.721 0.148 DPP10 2 0.7 2q14.1 One One 0 2 0 100 0.219 0.624 0.585 DROSHA 3 One 5p13.3 0 3 0 3 0 100 0.101 0.622 0.504 EYS 3 One 6q12 One 2 0 3 0 100 0.101 0.605 0.532 FAM161B One 0.3 NA 0 One 0 One 0 100 0.34 0.776 0.713 FLG 5 1.7 1q21.3 One 4 0 5 0 100 0.031 0.378 0.653 GAB4 3 One 22q11.1 0 3 0 3 0 100 0.096 0.658 0.532 HDAC7 2 0.7 12q13.11 0 2 0 2 0 100 0.176 0.538 0.487 HIVEP3 3 One 1p34.2 One 2 0 3 0 100 0.096 0.104 0.344 IL17RC 3 One 3p25.3|3p25.3-p24.1 0 3 0 3 0 100 0.096 0.625 0.507 KIAA1244 3 One NA 0 2 One 3 0 100 0.096 0.805 0.717 KIDINS220 2 0.7 2p25.1 2 0 0 2 0 100 0.176 0.529 0.487 KIF5A 3 One 12q13.3 0 3 0 3 0 100 0.096 0.598 0.477 LPIN1 3 One 2p25.1 One 2 0 3 0 100 0.096 0.401 0.281 MAPK6 2 0.7 15q21.2 One One 0 2 0 100 0.176 0.632 0.53 MDN1 3 One 6q15 0 3 0 3 0 100 0.096 0.615 0.503 MFSD10 2 0.7 4p16.3 0 2 0 2 0 100 0.176 0.637 0.185 MSTN 2 0.7 2q32.2 0 2 0 2 0 100 0.176 0.534 0.475 MYBBP1A 2 0.7 17p13.2 0 2 0 2 0 100 0.176 0.618 0.522 NCOA1 3 One 2p23.3 One 2 0 3 0 100 0.096 0.534 0.449 NCOA2 4 1.4 8q13.3 3 One 0 3 0 100 0.096 0.539 0.401 NPY2R 2 0.7 4q32.1 0 2 0 2 0 100 0.176 0.628 0.529 PUM1 3 One 1p35.2 0 3 0 3 0 100 0.096 0.572 0.504 R3HDM2 2 0.7 12q13.3 0 2 0 2 0 100 0.176 0.656 0.562 RGSL1 2 0.7 1q25.3 One One 0 2 0 100 0.176 0.687 0.603 SLC17A8 2 0.7 12q23.1 One One 0 2 0 100 0.176 0.722 0.641 SLC22A23 2 0.7 6p25.2 One One 0 2 0 100 0.176 0.28 0.585 SORL1 3 One 11q24.1 0 3 0 3 0 100 0.096 0.42 0.376 SSC5D 2 0.7 19q13.42 One One 0 2 0 100 0.176 0.016 0.743 TMEM254 One 0.3 NA 0 One 0 One 0 100 0.34 0.722 0.638 VWA8 3 One 13q14.11 0 3 0 3 0 100 0.096 0.621 0.515 WAPAL 3 One NA 0 3 0 3 0 100 0.096 0.604 0.403 WDR20 3 One 14q32.31 One 2 0 3 0 100 0.096 0.391 0.547 WWC2 2 0.7 4q35.1 0 2 0 2 0 100 0.176 0.457 0.335 ZC3H13 2 0.7 13q14.13 One One 0 2 0 100 0.176 0.667 0.574 ZER1 3 One 9q34.11 One 2 0 3 0 100 0.096 0.661 0.173

Among these 52 genes, 48 genes with a p value of 0.05 or higher in Fisher's exact test are related to tumor type, but the correlation is low. In addition, the following four genes with a p value of less than 0.05 (candidate gene group 1) are considered to be highly correlated with the tumor type, and specifically, if there is a mutation in the corresponding gene, the tumor type can be determined as Type 1.

Candidate gene group 1: DDX20, FLG, KYAT3.

Selection and review of tumor type-specific markers for prognosis prediction

In order to confirm the possibility of use as a tumor type-specific marker for prognosis prediction, comparative analysis was performed on the data of the 162 subjects for them, and missing values and outliers were excluded:

Based on the clinical information (event (death or recurrence), observation time) of the patients, overall survival or disease-free survival was calculated by Kaplan Meier survival analysis using SPSS. In the total survival period, the event was defined as death, and in the disease-free survival period, the event was defined as the recurrence of renal cancer. In order to determine whether the occurrence of mutations in each of the genes is correlated with death or recurrence of kidney cancer, based on the event time of each group obtained in the Kaplan Meier survival assay, The association of total survival and the association of mutagenesis and disease-free survival were confirmed by log rank test. A p-value of less than 0.05 was considered statistically significant.

The experimental group was defined as the case with alterations in query gene, and the control group was the case without alterations in query gene. The median months survival means a value located at the center when the survival periods of patients in the corresponding group are listed. The slope in the survival curve by the Kaplan Meier survival assay is determined by the duration of survival.

As a result of the above analysis, the following one gene (candidate gene group 2) with a p-value of less than 0.05 for total survival is considered a gene highly correlated with the survival rate or recurrence rate. Specifically, if there is a mutation in the gene, the survival rate is low or The recurrence rate is considered high.

Candidate gene group 2: SSC5D.

First, with respect to the three genes of the first group of candidate genes that are related to the tumor type, FIG. 1 shows a kidney cancer patient with a mutation in the corresponding gene (red) and a kidney cancer patient without a mutation in the corresponding gene (blue). graphs of the total survival rate and disease-free survival rate of In FIG. 1 , the p values of the total survival rate and the disease-free survival rate are 0.05 or higher, indicating that the genes have a low correlation with the total survival rate and the disease-free survival rate.

Next, with respect to the SSC5D gene of the second group of candidate genes that are correlated with the survival rate, FIG. 2 shows a kidney cancer patient with a mutation in the corresponding gene (red) and a kidney cancer patient without a mutation in the corresponding gene (blue). Graphs of total survival and disease-free survival are shown. In FIG. 2 , since the p value of the total survival rate is 0.0161, which is less than 0.05, the gene appears to be highly correlated with the total survival rate. Therefore, if there is a mutation in the gene, it may be determined that the overall survival rate is low.

3 is a graph of the total survival rate and disease-free survival rate of a kidney cancer patient with a mutation in the gene (red) and a kidney cancer patient without a mutation in the gene (blue) for a total of 52 genes related to the tumor type. indicates.

Detection of marker genes using mutation position information

Mutation position information of the genes of the first group and the second group of candidate genes is shown below.

Gene AA change Type Copy # COSMIC Chr Start Pos End Pos HGVSc DDX20 L126F Missense diploid One 112299342 112299342 ENST00000369702.4:c.376C>T T113S Missense diploid One 112299304 112299304 ENST00000369702.4:c.338C>G F315C Missense diploid One One 112303729 112303729 ENST00000369702.4:c.944T>G E709K Missense gain One One 112309171 112309171 ENST00000369702.4:c.2125G>A FLG H822N Missense diploid One One 152284898 152284898 ENST00000368799.1:c.2464C>A G2564* Nonsense diploid One One 152279672 152279672 ENST00000368799.1:c.7690G>T R3780T Missense diploid One One 152276023 152276023 ENST00000368799.1:c.11339G>C E3429D Missense diploid One One 152277075 152277075 ENST00000368799.1:c.10287G>T S2029C Missense amp One One 152281276 152281276 ENST00000368799.1:c.6086C>G KYAT3 T309K Missense diploid One 89418774 89418774 ENST00000260508.4:c.926C>A K399* Nonsense diploid One 89409053 89409053 ENST00000260508.4:c.1195A>T K399Nfs*3 Frame_Shift_Del diploid One 89409051 89409051 ENST00000260508.4:c.1197delA K399Mfs*4 Frame_Shift_Del diploid One 89409052 89409053 ENST00000260508.4:c.1196_1197delAA SSC5D W801Gfs*22 Frame_Shift_Del diploid 19 56011955 56011955 ENST00000389623.6:c.2401delT S1077R Missense diploid 19 56028874 56028874 ENST00000389623.6:c.3231T>A

Based on the mutation position information, it is possible to manufacture a microchip using a primer, a probe, an antibody, or an aptamer capable of detecting the marker gene, and the specific method may be according to a conventional technique.

In the above, preferred embodiments of the present invention have been exemplarily described, but the scope of the present invention is not limited to the specific embodiments as described above, and those of ordinary skill in the art will It can be appropriately changed within.

<110> THE CATHOLIC UNIVERSITY OF KOREA INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Composition And Kit For Diagnosing Prognosis Of Kidney Cancer According To Tumor Type <130> 2021-DPA-4414D <150> KR 10-2020-0010280 <151> 2020-01-29 <160> 4 <170> KoPatentIn 3.0 <210> 1 <211> 1573 <212> PRT <213> Homo sapiens <400> 1 Met Arg Val Leu Ala Cys Leu Leu Ala Ala Leu Val Gly Ile Gln Ala 1 5 10 15 Val Glu Arg Leu Arg Leu Ala Asp Gly Pro His Gly Cys Ala Gly Arg 20 25 30 Leu Glu Val Trp His Gly Gly Arg Trp Gly Thr Val Cys Asp Asp Gly 35 40 45 Trp Asp Leu Arg Asp Ala Ala Val Ala Cys Arg Gln Leu Gly Cys Gly 50 55 60 Gly Ala Leu Ala Ala Pro Gly Gly Ala Phe Phe Gly Glu Gly Ala Gly 65 70 75 80 Pro Val Trp Leu Ser Glu Leu Ala Cys Arg Gly Asn Glu Gly Gln Leu 85 90 95 Gly Leu Cys His His Arg Gly Trp Lys Ala His Ile Cys Ser His Glu 100 105 110 Glu Asp Ala Gly Val Val Cys Ala Gly Gln Arg Val Ala Asn Ser Arg 115 120 125 Asp Asp Ser Thr Ser Pro Leu Asp Gly Ala Pro Trp Pro Gly Leu Leu 130 135 140 Leu Glu Leu Ser Pro Ser Thr Glu Glu Pro Leu Val Thr His Ala Pro 145 150 155 160 Arg Pro Ala Gly Asn Pro Gln Asn Ala Ser Arg Lys Lys Ser Pro Arg 165 170 175 Pro Lys Gln Ala Lys Ser Thr Arg Ala Pro Leu Leu Thr Thr Gly Ala 180 185 190 Pro Arg Gln Glu Arg Leu Arg Leu Val Ser Gly Pro His Arg Cys Ala 195 200 205 Gly Arg Leu Glu Val Trp His Gly Gly Arg Trp Gly Thr Val Cys Asp 210 215 220 Asp Gly Trp Asp Leu Arg Asp Ala Ala Val Ala Cys Arg Glu Leu Gly 225 230 235 240 Cys Gly Gly Ala Leu Ala Ala Pro Gly Gly Ala Arg Phe Gly Pro Gly 245 250 255 Ala Gly Pro Val Trp Met Asp Asp Val Gly Cys Gly Gly Gly Glu Gln 260 265 270 Ala Leu Arg Asp Cys Pro Arg Ser Pro Trp Gly Arg Ser Asn Cys Asp 275 280 285 His Ser Glu Asp Ala Gly Leu Val Cys Thr Gly Pro Ala Pro Arg Leu 290 295 300 Arg Leu Ala Asp Gly Pro His Gly Cys Ala Gly Arg Leu Glu Val Trp 305 310 315 320 His Gly Gly Arg Trp Gly Ser Val Cys Asp Asp Ala Trp Asp Leu Arg 325 330 335 Asp Ala Ala Val Ala Cys Arg Glu Leu Gly Cys Gly Gly Ala Leu Ala 340 345 350 Ala Pro Gly Gly Ala Phe Phe Gly Glu Gly Ser Gly Pro Ile Ile Leu 355 360 365 Asp Asp Leu Arg Cys Arg Gly Asn Glu Thr Ala Leu Arg Phe Cys Pro 370 375 380 Ala Arg Pro Trp Gly Gln His Asp Cys His His Arg Glu Asp Ala Gly 385 390 395 400 Ala Val Cys Asp Gly Met Pro Leu Gly Tyr Val Pro Pro Thr Ala Pro 405 410 415 Thr Asp Ser Asn Asn Ser Thr Pro Arg Glu Ala Ala Ser Arg Pro Pro 420 425 430 Ser Thr Met Thr Ser Gln Ala Pro Gly Thr Ala Gly Val Ser Pro Pro 435 440 445 Pro Ala Ser Pro Thr Val Leu Trp Glu Pro Gly Pro Glu Ala Gly Ser 450 455 460 Pro Gln Leu Arg Leu Val Ala Gly Pro Ser Lys Cys Ser Gly Arg Leu 465 470 475 480 Glu Val Trp His Asp Gln Arg Trp Gly Thr Val Cys Asp Asp Ser Trp 485 490 495 Asp Met Arg Asp Ser Ala Val Val Cys Arg Glu Leu Gly Cys Gly Gly 500 505 510 Pro Gln Gln Pro Asp Pro Ala Ala Gly Arg Phe Gly Trp Gly Ala Gly 515 520 525 Pro Ile Trp Leu Asp Asp Val Gly Cys Val Gly Thr Glu Ala Ser Leu 530 535 540 Ser Asp Cys Pro Ala Ala Pro Trp Gly Lys His Asn Cys Ala His Asn 545 550 555 560 Glu Asp Val Gly Val Thr Cys Thr Gly Pro Gly Leu Asp Ser Ile 565 570 575 Ser Asp Pro Phe Ser Trp Ser Trp Ile Pro Gly Leu Gly Arg Asp Arg 580 585 590 Asp Ala Trp Leu Pro Gly Glu Leu Ala Thr Lys Pro Ser Ala Ser Val 595 600 605 Thr Ala Ser Val Leu Glu Lys Thr Thr Thr Lys Ala Pro Gly Lys Met 610 615 620 Pro Lys Ser Thr Lys Lys Trp Val Thr Lys Asn Ala Lys Arg Pro Thr 625 630 635 640 Thr Gln Pro Pro Val Met Pro Thr Thr Lys His Ser Arg Ala Gln Ser 645 650 655 Pro Pro Asp Leu Thr Ser Gln Thr Thr Ala Ala Leu Thr Thr Glu Ala 660 665 670 Ser Arg Arg Pro Thr Ser Glu Phe Thr Arg Arg Pro Thr Thr Glu Ala 675 680 685 Pro Gln Arg Trp Thr Ser His Thr Thr Ala Thr Leu Thr Pro Gln Ala 690 695 700 Pro Arg Glu Arg Thr Thr Lys Thr Met Ala Met Leu Thr Thr Gln Gly 705 710 715 720 Pro Gln Glu Met Thr Ser Glu Ser Thr Ile Lys Ser Ile Pro Gln Ala 725 730 735 Ser Leu Glu Pro Ser Ala Glu Ile Pro Glu Gly Ser Pro Glu Ser Pro 740 745 750 Lys Asp Pro Ala Pro Ser Pro Ser Val Ser Thr Thr Gly Glu Ser Gly 755 760 765 Leu Phe Arg Val Arg Leu Ala Asp Gly Pro Asn Arg Cys Ala Gly Arg 770 775 780 Leu Glu Val Trp His Ala Gly Arg Trp Gly Thr Val Cys Asp Asp Asn 785 790 795 800 Trp Asp Leu Arg Asp Ala Thr Val Ala Cys Trp Glu Leu Gly Cys Gly 805 810 815 Lys Val Arg Pro Arg Val Gly Lys Thr His Tyr Gly Pro Gly Thr Gly 820 825 830 Pro Ile Trp Leu Asp Asp Met Gly Cys Lys Gly Ser Glu Ala Ser Leu 835 840 845 Ser Asp Cys Pro Ser Gly Ala Trp Gly Lys His Asn Cys Asp His Glu 850 855 860 Glu Asp Val Gly Leu Thr Cys Thr Gly Tyr Thr Asp Tyr Asp Asp Tyr 865 870 875 880 Pro Pro Trp Thr Trp Asp Pro Thr Ser Arg Glu Asp Leu Ala Lys Gly 885 890 895 Thr Thr Thr Ala Gly Val Pro Gly His Thr Leu Pro Trp Arg Thr Thr 900 905 910 Arg Arg Pro Gly Ser Ser Ser Pro Ala Ile Arg Arg Leu Pro Asp Thr 915 920 925 Gly Ser Lys Asp Gly Tyr Lys Leu Pro Trp Thr Trp Asp Thr Pro Ser 930 935 940 Gly Arg Gly Leu Ala Glu Gly Thr Pro Thr Ala Gly Lys Leu Gly Pro 945 950 955 960 Thr Leu Gly Ala Gly Thr Thr Arg Ser Pro Gly Ser Pro Pro Thr Leu 965 970 975 Arg Val His Gly Asp Thr Gly Ser Pro Arg Lys Pro Trp Pro Glu Arg 980 985 990 Arg Pro Pro Arg Pro Ala Ala Thr Arg Thr Ala Pro Pro Thr Pro Ser 995 1000 1005 Pro Gly Pro Ser Ala Ser Pro Gly Pro Pro Gly Pro Ala Leu Thr Ser 1010 1015 1020 Asp Ser Ser Arg Glu Leu Thr Pro His Ser Ala Leu Thr Ser Glu Ala 1025 1030 1035 1040 Thr Ser Asp Ala Pro Asp Thr Ser Pro Pro Thr Pro Asp Pro Ala Ser 1045 1050 1055 Arg Thr Asn Pro Asp Leu Ile Leu Thr Ser Pro Asp Phe Ala Leu Ser 1060 1065 1070 Thr Pro Asp Ser Ser Val Val Pro Ala Leu Thr Pro Glu Pro Ser Pro 1075 1080 1085 Thr Pro Leu Pro Thr Leu Pro Lys Glu Leu Thr Ser Asp Pro Ser Thr 1090 1095 1100 Pro Ser Glu Val Thr Ser Leu Ser Pro Thr Ser Glu Gln Val Pro Glu 1105 1110 1115 1120 Ser Asp Thr Thr Pro Asp Leu Asp Thr Thr Pro Tyr Ser Ser Thr Val 1125 1130 1135 Ser Glu Tyr Ser Arg Ser Pro Asp Pro Ser Pro Ser Pro His Pro Thr 1140 1145 1150 Thr Thr Pro Asp Pro Thr Met Ala Pro Asp Pro Ile Thr Thr Leu Asn 1155 1160 1165 Pro Thr Val Thr Pro His Phe Pro Thr Thr Pro His Pro Thr Thr Thr 1170 1175 1180 Pro His Pro Thr Thr Ile Thr His Ser Thr Met Ile Pro Asp Pro Thr 1185 1190 1195 1200 Thr Thr Pro Gln Pro Phe Thr Thr Ile Thr His Ser Thr Met Ile Pro 1205 1210 1215 Asp Pro Thr Thr Thr Pro Gln Pro Phe Thr Thr Met Gln Pro Thr Thr 1220 1225 1230 Thr Pro His Ser Thr Thr Pro His Pro Thr Thr Thr Pro His Pro Thr 1235 1240 1245 Thr Ile Thr His Ser Thr Met Ile Pro Asp Pro Thr Thr Thr Pro Gln 1250 1255 1260 Pro Phe Thr Thr Met Gln Pro Thr Thr Met Pro His Pro Thr Thr Thr 1265 1270 1275 1280 Pro His Pro Thr Thr Thr Pro His Pro Thr Thr Thr Pro His Pro Thr 1285 1290 1295 Thr Thr Pro His Pro Thr Met Thr Pro Asp Pro Thr Thr Thr Pro Tyr 1300 1305 1310 Pro Thr Thr Thr Pro Asp Pro Thr Thr Thr Pro His Pro Thr Thr Pro 1315 1320 1325 Asp Pro Ser Ser Thr Pro Val Ile Thr Thr Val Ser Leu Pro Thr Ser 1330 1335 1340 Leu Gly Thr Glu Leu Ser Ser Pro Thr Leu Ala Pro Thr Val Lys Pro 1345 1350 1355 1360 Ser Leu His Pro Gln Leu Thr Phe Thr Ala Pro Ala Pro His Thr Ser 1365 1370 1375 Thr Ser Gln Ile Pro Thr Leu Glu Pro Ser Pro Ala Leu Glu Ser Ser 1380 1385 1390 Pro Ser Arg Ser Ser Thr Ala Thr Ser Met Asp Pro Leu Ser Thr Glu 1395 1400 1405 Asp Phe Lys Pro Pro Arg Ser Gln Ser Pro Asn Leu Thr Pro Pro Pro 1410 1415 1420 Thr His Thr Pro His Ser Ala Ser Asp Leu Thr Val Ser Pro Asp Pro 1425 1430 1435 1440 Leu Leu Ser Pro Thr Ala His Pro Leu Asp His Pro Pro Leu Asp Pro 1445 1450 1455 Leu Thr Leu Gly Pro Thr Pro Gly Gln Ser Pro Gly Pro His Gly Pro 1460 1465 1470 Cys Val Ala Pro Thr Pro Pro Val Arg Val Met Ala Cys Glu Pro Pro 1475 1480 1485 Ala Leu Val Glu Leu Val Ala Ala Val Arg Asp Val Gly Gly Gln Leu 1490 1495 1500 Gln Arg Leu Thr Gln Val Val Glu Gln Glu Arg Gln Glu Arg Gln Ala 1505 1510 1515 1520 Leu Leu Leu Gly Leu Thr Gln Leu Val Glu Ala Ala Arg Gly Leu Gly 1525 1530 1535 Gln Leu Gly Glu Ala Val Lys Arg Leu Ala Glu Met Ala Trp Thr Thr 1540 1545 1550 Ser Met Pro Ala Pro Thr Thr Thr Thr Pro Glu Glu Glu Glu Arg Pro 1555 1560 1565 Leu Arg Gly Asp Val 1570 <210> 2 <211> 824 <212> PRT <213> Homo sapiens <400> 2 Met Ala Ala Ala Phe Glu Ala Ser Gly Ala Leu Ala Ala Val Ala Thr 1 5 10 15 Ala Met Pro Ala Glu His Val Ala Val Gln Val Pro Ala Pro Glu Pro 20 25 30 Thr Pro Gly Pro Val Arg Ile Leu Arg Thr Ala Gln Asp Leu Ser Ser 35 40 45 Pro Arg Thr Arg Thr Gly Asp Val Leu Leu Ala Glu Pro Ala Asp Phe 50 55 60 Glu Ser Leu Leu Leu Ser Arg Pro Val Leu Glu Gly Leu Arg Ala Ala 65 70 75 80 Gly Phe Glu Arg Pro Ser Pro Val Gln Leu Lys Ala Ile Pro Leu Gly 85 90 95 Arg Cys Gly Leu Asp Leu Ile Val Gln Ala Lys Ser Gly Thr Gly Lys 100 105 110 Thr Cys Val Phe Ser Thr Ile Ala Leu Asp Ser Leu Val Leu Glu Asn 115 120 125 Leu Ser Thr Gln Ile Leu Ile Leu Ala Pro Thr Arg Glu Ile Ala Val 130 135 140 Gln Ile His Ser Val Ile Thr Ala Ile Gly Ile Lys Met Glu Gly Leu 145 150 155 160 Glu Cys His Val Phe Ile Gly Gly Thr Pro Leu Ser Gln Asp Lys Thr 165 170 175 Arg Leu Lys Lys Cys His Ile Ala Val Gly Ser Pro Gly Arg Ile Lys 180 185 190 Gln Leu Ile Glu Leu Asp Tyr Leu Asn Pro Gly Ser Ile Arg Leu Phe 195 200 205 Ile Leu Asp Glu Ala Asp Lys Leu Leu Glu Glu Gly Ser Phe Gln Glu 210 215 220 Gln Ile Asn Trp Ile Tyr Ser Ser Leu Pro Ala Ser Lys Gln Met Leu 225 230 235 240 Ala Val Ser Ala Thr Tyr Pro Glu Phe Leu Ala Asn Ala Leu Thr Lys 245 250 255 Tyr Met Arg Asp Pro Thr Phe Val Arg Leu Asn Ser Ser Asp Pro Ser 260 265 270 Leu Ile Gly Leu Lys Gln Tyr Tyr Lys Val Val Asn Ser Tyr Pro Leu 275 280 285 Ala His Lys Val Phe Glu Glu Lys Thr Gln His Leu Gln Glu Leu Phe 290 295 300 Ser Arg Ile Pro Phe Asn Gln Ala Leu Val Phe Ser Asn Leu His Ser 305 310 315 320 Arg Ala Gln His Leu Ala Asp Ile Leu Ser Ser Lys Gly Phe Pro Ala 325 330 335 Glu Cys Ile Ser Gly Asn Met Asn Gln Asn Gln Arg Leu Asp Ala Met 340 345 350 Ala Lys Leu Lys His Phe His Cys Arg Val Leu Ile Ser Thr Asp Leu 355 360 365 Thr Ser Arg Gly Ile Asp Ala Glu Lys Val Asn Leu Val Val Asn Leu 370 375 380 Asp Val Pro Leu Asp Trp Glu Thr Tyr Met His Arg Ile Gly Arg Ala 385 390 395 400 Gly Arg Phe Gly Thr Leu Gly Leu Thr Val Thr Tyr Cys Cys Arg Gly 405 410 415 Glu Glu Glu Asn Met Met Met Arg Ile Ala Gln Lys Cys Asn Ile Asn 420 425 430 Leu Leu Pro Leu Pro Asp Pro Ile Pro Ser Gly Leu Met Glu Glu Cys 435 440 445 Val Asp Trp Asp Val Glu Val Lys Ala Ala Val His Thr Tyr Gly Ile 450 455 460 Ala Ser Val Pro Asn Gln Pro Leu Lys Lys Gln Ile Gln Lys Ile Glu 465 470 475 480 Arg Thr Leu Gln Ile Gln Lys Ala His Gly Asp His Met Ala Ser Ser 485 490 495 Arg Asn Asn Ser Val Ser Gly Leu Ser Val Lys Ser Lys Asn Asn Thr 500 505 510 Lys Gln Lys Leu Pro Val Lys Ser His Ser Glu Cys Gly Ile Ile Glu 515 520 525 Lys Ala Thr Ser Pro Lys Glu Leu Gly Cys Asp Arg Gln Ser Glu Glu 530 535 540 Gln Met Lys Asn Ser Val Gln Thr Pro Val Glu Asn Ser Thr Asn Ser 545 550 555 560 Gln His Gln Val Lys Glu Ala Leu Pro Val Ser Leu Pro Gln Ile Pro 565 570 575 Cys Leu Ser Ser Phe Lys Ile His Gln Pro Tyr Thr Leu Thr Phe Ala 580 585 590 Glu Leu Val Glu Asp Tyr Glu His Tyr Ile Lys Glu Gly Leu Glu Lys 595 600 605 Pro Val Glu Ile Ile Arg His Tyr Thr Gly Pro Gly Asp Gln Thr Val 610 615 620 Asn Pro Gln Asn Gly Phe Val Arg Asn Lys Val Ile Glu Gln Arg Val 625 630 635 640 Pro Val Leu Ala Ser Ser Ser Gln Ser Gly Asp Ser Glu Ser Asp Ser 645 650 655 Asp Ser Tyr Ser Ser Arg Thr Ser Ser Gln Ser Lys Gly Asn Lys Ser 660 665 670 Tyr Leu Glu Gly Ser Ser Asp Asn Gln Leu Lys Asp Ser Glu Ser Thr 675 680 685 Pro Val Asp Asp Arg Ile Ser Leu Glu Gln Pro Pro Asn Gly Ser Asp 690 695 700 Thr Pro Asn Pro Glu Lys Tyr Gln Glu Ser Pro Gly Ile Gln Met Lys 705 710 715 720 Thr Arg Leu Lys Glu Gly Ala Ser Gln Arg Ala Lys Gln Ser Arg Arg 725 730 735 Asn Leu Pro Arg Arg Ser Ser Phe Arg Leu Gln Thr Glu Ala Gln Glu 740 745 750 Asp Asp Trp Tyr Asp Cys His Arg Glu Ile Arg Leu Ser Phe Ser Asp 755 760 765 Thr Tyr Gln Asp Tyr Glu Glu Tyr Trp Arg Ala Tyr Tyr Arg Ala Trp 770 775 780 Gln Glu Tyr Tyr Ala Ala Ala Ser His Ser Tyr Tyr Trp Asn Ala Gln 785 790 795 800 Arg His Pro Ser Trp Met Ala Ala Tyr His Met Asn Thr Ile Tyr Leu 805 810 815 Gln Glu Met Met His Ser Asn Gln 820 <210> 3 <211> 4061 <212> PRT <213> Homo sapiens <400> 3 Met Ser Thr Leu Leu Glu Asn Ile Phe Ala Ile Ile Asn Leu Phe Lys 1 5 10 15 Gln Tyr Ser Lys Lys Asp Lys Asn Thr Asp Thr Leu Ser Lys Lys Glu 20 25 30 Leu Lys Glu Leu Leu Glu Lys Glu Phe Arg Gln Ile Leu Lys Asn Pro 35 40 45 Asp Asp Pro Asp Met Val Asp Val Phe Met Asp His Leu Asp Ile Asp 50 55 60 His Asn Lys Lys Ile Asp Phe Thr Glu Phe Leu Leu Met Val Phe Lys 65 70 75 80 Leu Ala Gln Ala Tyr Tyr Glu Ser Thr Arg Lys Glu Asn Leu Pro Ile 85 90 95 Ser Gly His Lys His Arg Lys His Ser His His Asp Lys His Glu Asp 100 105 110 Asn Lys Gln Glu Glu Asn Lys Glu Asn Arg Lys Arg Pro Ser Ser Leu 115 120 125 Glu Arg Arg Asn Asn Arg Lys Gly Asn Lys Gly Arg Ser Lys Ser Pro 130 135 140 Arg Glu Thr Gly Gly Lys Arg His Glu Ser Ser Ser Glu Lys Lys Glu 145 150 155 160 Arg Lys Gly Tyr Ser Pro Thr His Arg Glu Glu Glu Tyr Gly Lys Asn 165 170 175 His His Asn Ser Ser Lys Lys Glu Lys Asn Lys Thr Glu Asn Thr Arg 180 185 190 Leu Gly Asp Asn Arg Lys Arg Leu Ser Glu Arg Leu Glu Glu Lys Glu 195 200 205 Asp Asn Glu Glu Gly Val Tyr Asp Tyr Glu Asn Thr Gly Arg Met Thr 210 215 220 Gln Lys Trp Ile Gln Ser Gly His Ile Ala Thr Tyr Tyr Thr Ile Gln 225 230 235 240 Asp Glu Ala Tyr Asp Thr Thr Asp Ser Leu Leu Glu Glu Asn Lys Ile 245 250 255 Tyr Glu Arg Ser Arg Ser Ser Asp Gly Lys Ser Ser Ser Gln Val Asn 260 265 270 Arg Ser Arg His Glu Asn Thr Ser Gln Val Pro Leu Gln Glu Ser Arg 275 280 285 Thr Arg Lys Arg Arg Gly Ser Arg Val Ser Gln Asp Arg Asp Ser Glu 290 295 300 Gly His Ser Glu Asp Ser Glu Arg His Ser Gly Ser Ala Ser Arg Asn 305 310 315 320 His His Gly Ser Ala Trp Glu Gln Ser Arg Asp Gly Ser Arg His Pro 325 330 335 Arg Ser His Asp Glu Asp Arg Ala Ser His Gly His Ser Ala Asp Ser 340 345 350 Ser Arg Gln Ser Gly Thr Arg His Ala Glu Thr Ser Ser Arg Gly Gln 355 360 365 Thr Ala Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His 370 375 380 Gly Ser Gly His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Ala Thr 385 390 395 400 Gly Arg Gly Gln Ala Ser Ser Ala Val Ser Asp Arg Gly His Arg Gly 405 410 415 Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asn Ser 420 425 430 Asp Thr Gln Ser Val Ser Gly His Gly Lys Ala Gly Leu Arg Gln Gln 435 440 445 Ser His Gln Glu Ser Thr Arg Gly Arg Ser Gly Glu Arg Ser Gly Arg 450 455 460 Ser Gly Ser Ser Leu Tyr Gln Val Ser Thr His Glu Gln Pro Asp Ser 465 470 475 480 Ala His Gly Arg Thr Gly Thr Ser Thr Gly Gly Arg Gln Gly Ser His 485 490 495 His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly 500 505 510 Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln 515 520 525 Gly Ser His His Glu Gln Ser Val Asn Arg Ser Gly His Ser Gly Ser 530 535 540 His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly 545 550 555 560 Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu Gln 565 570 575 Ser Gly Asp Gly Thr Arg His Ser Gly Ser Arg His His Glu Ala Ser 580 585 590 Ser Gln Ala Asp Ser Ser Arg His Ser Gln Val Gly Gly Gly Gln Ser 595 600 605 Ser Gly Pro Arg Thr Ser Arg Asn Gin Gly Ser Ser Val Ser Gln Asp 610 615 620 Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser 625 630 635 640 Ala Ser Arg Asn His His Gly Ser Ala Gln Glu Gln Ser Arg Asp Gly 645 650 655 Ser Arg His Pro Arg Ser His His Glu Asp Arg Ala Gly His Gly His 660 665 670 Ser Ala Asp Ser Ser Arg Lys Ser Gly Thr Arg His Thr Gln Asn Ser 675 680 685 Ser Ser Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala 690 695 700 Gly Glu Arg His Gly Ser Arg His Gln Leu Gln Ser Ala Asp Ser Ser 705 710 715 720 Arg His Ser Gly Thr Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp 725 730 735 Ser Gly His Arg Gly Ser Ser Gly Ser Gln Ala Thr Asp Ser Glu Gly 740 745 750 His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Gly His Gly Gln Ala 755 760 765 Gly His His Gln Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser Gly 770 775 780 Glu Arg Ser Arg Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His 785 790 795 800 Lys Gln Ser Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Gly Val 805 810 815 Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Asn Ser Arg His Ser 820 825 830 Ala Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser 835 840 845 Arg Arg Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp Arg Ser 850 855 860 Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser 865 870 875 880 Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr 885 890 895 Arg Asn Glu Glu Gln Ser Arg Asp Gly Ser Arg His Ser Gly Ser Arg 900 905 910 His His Glu Ala Ser Ser His Ala Asp Ile Ser Arg His Ser Gln Ala 915 920 925 Gly Gln Gly Gln Ser Glu Gly Ser Arg Thr Ser Arg Arg Gln Gly Ser 930 935 940 Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu 945 950 955 960 Arg Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu 965 970 975 Gln Ser Arg His Gly Ser Arg His Pro Arg Ser His His Glu Asp Arg 980 985 990 Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Pro 995 1000 1005 His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu Gln 1010 1015 1020 Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg His Gln Gln Ser 1025 1030 1035 1040 Ala Asp Ser Ser Arg His Ser Gly Ile Pro Arg Arg Gln Ala Ser Ser 1045 1050 1055 Ala Val Arg Asp Ser Gly His Trp Gly Ser Ser Gly Ser Gln Ala Ser 1060 1065 1070 Asp Ser Glu Gly His Ser Glu Glu Ser Asp Thr Gln Ser Val Ser Gly 1075 1080 1085 His Gly Gln Asp Gly Pro His Gln Gln Ser His Gln Glu Ser Ala Arg 1090 1095 1100 Asp Trp Ser Gly Gly Arg Ser Gly Arg Ser Gly Ser Phe Ile Tyr Gln 1105 1110 1115 1120 Val Ser Thr His Glu Gin Ser Glu Ser Ala His Gly Arg Thr Arg Thr 1125 1130 1135 Ser Thr Gly Arg Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Ser 1140 1145 1150 Ser Arg His Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Ala His 1155 1160 1165 Pro Gly Ser Arg Arg Gly Gly Arg Gln Gly Ser His His Glu Gln Ser 1170 1175 1180 Val Asp Arg Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser 1185 1190 1195 1200 Gln Gly Arg Ser Asp Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala 1205 1210 1215 Ser Arg Gln Thr Arg Lys Asp Lys Gln Ser Gly Asp Gly Ser Arg His 1220 1225 1230 Ser Gly Ser Arg His His Glu Ala Ala Ser Trp Ala Asp Ser Ser Arg 1235 1240 1245 His Ser Gln Val Gly Gin Glu Gln Ser Ser Gly Ser Arg Thr Ser Arg 1250 1255 1260 His Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Arg His Ser 1265 1270 1275 1280 Asp Asp Ser Glu Arg Leu Ser Gly Ser Ala Ser Arg Asn His His Gly 1285 1290 1295 Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His Pro Gly Phe His 1300 1305 1310 Gln Glu Asp Arg Ala Ser His Gly His Ser Ala Asp Ser Ser Ser Arg Gln 1315 1320 1325 Ser Gly Thr His His Thr Glu Ser Ser Ser His Gly Gln Ala Val Ser 1330 1335 1340 Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg 1345 1350 1355 1360 His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Arg 1365 1370 1375 Gln Ala Ser Ser Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly 1380 1385 1390 Ser Gln Val Thr Asn Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln 1395 1400 1405 Ser Val Ser Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His Lys 1410 1415 1420 Glu Ser Ala Arg Gly Gln Ser Gly Glu Ser Ser Gly Arg Ser Arg Ser 1425 1430 1435 1440 Phe Leu Tyr Gln Val Ser Ser His Glu Gln Ser Glu Ser Thr His Gly 1445 1450 1455 Gln Thr Ala Pro Ser Thr Gly Gly Arg Gln Gly Ser Arg His Glu Gln 1460 1465 1470 Ala Arg Asn Ser Ser Arg His Ser Ala Ser Gln Asp Gly Gln Asp Thr 1475 1480 1485 Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly Ser Tyr 1490 1495 1500 His Glu Gln Ser Val Asp Arg Ser Gly His Ser Gly Tyr His His Ser 1505 1510 1515 1520 His Thr Thr Pro Gln Gly Arg Ser Asp Ala Ser His Gly Gln Ser Gly 1525 1530 1535 Pro Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu Gln Ser Gly Asp 1540 1545 1550 Gly Ser Arg His Ser Gly Ser Arg His His Glu Pro Ser Thr Arg Ala 1555 1560 1565 Gly Ser Ser Arg His Ser Gln Val Gly Gln Gly Glu Ser Ala Gly Ser 1570 1575 1580 Lys Thr Ser Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Arg Asp Ser 1585 1590 1595 1600 Glu Gly His Ser Glu Asp Ser Glu Arg Arg Ser Glu Ser Ala Ser Arg 1605 1610 1615 Asn His Tyr Gly Ser Ala Arg Glu Gln Ser Arg His Gly Ser Arg Asn 1620 1625 1630 Pro Arg Ser His Gln Glu Asp Arg Ala Ser His Gly His Ser Ala Glu 1635 1640 1645 Ser Ser Arg Gln Ser Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly 1650 1655 1660 Gln Ala Ala Ser Ser Gln Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg 1665 1670 1675 1680 His Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser Thr Asp Ser Gly 1685 1690 1695 Thr Gly Arg Arg Gln Asp Ser Ser Val Val Gly Asp Ser Gly Asn Arg 1700 1705 1710 Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu 1715 1720 1725 Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Pro His Gln 1730 1735 1740 Gln Ser His Gln Glu Ser Thr Arg Gly Gln Ser Gly Glu Arg Ser Gly 1745 1750 1755 1760 Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu 1765 1770 1775 Ser Ala His Gly Arg Thr Gly Pro Ser Thr Gly Gly Arg Gln Arg Ser 1780 1785 1790 Arg His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu 1795 1800 1805 Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg 1810 1815 1820 Gln Gly Ser His Tyr Glu Gln Ser Val Asp Ser Ser Gly His Ser Gly 1825 1830 1835 1840 Ser His His Ser His Thr Thr Ser Gln Glu Arg Ser Asp Val Ser Arg 1845 1850 1855 Gly Gln Ser Gly Ser Arg Ser Val Ser Arg Gln Thr Arg Asn Glu Lys 1860 1865 1870 Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala 1875 1880 1885 Ser Ser Arg Ala Asp Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln 1890 1895 1900 Ser Ser Gly Pro Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln 1905 1910 1915 1920 Asp Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly 1925 1930 1935 Ser Ala Ser Arg Asn His Leu Gly Ser Ala Trp Glu Gln Ser Arg Asp 1940 1945 1950 Gly Ser Arg His Pro Gly Ser His His Glu Asp Arg Ala Gly His Gly 1955 1960 1965 His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Glu Ser 1970 1975 1980 Ser Ser Arg Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser 1985 1990 1995 2000 Ala Gly Glu Arg His Gly Ser His His Gln Leu Gln Ser Ala Asp Ser 2005 2010 2015 Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg 2020 2025 2030 Asp Ser Gly His Arg Gly Tyr Ser Gly Ser Gln Ala Ser Asp Ser Glu 2035 2040 2045 Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala Gln Gly Lys 2050 2055 2060 Ala Gly Pro His Gln Gln Ser His Lys Glu Ser Ala Arg Gly Gln Ser 2065 2070 2075 2080 Gly Glu Ser Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr 2085 2090 2095 His Glu Gln Ser Glu Ser Thr His Gly Gln Ser Ala Pro Ser Thr Gly 2100 2105 2110 Gly Arg Gln Gly Ser His Tyr Asp Gln Ala Gln Asp Ser Ser Arg His 2115 2120 2125 Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro Gly Pro 2130 2135 2140 Ser Arg Gly Gly Arg Gln Gly Ser His Gln Glu Gln Ser Val Asp Arg 2145 2150 2155 2160 Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg 2165 2170 2175 Ser Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Lys 2180 2185 2190 Thr Tyr Asp Lys Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser 2195 2200 2205 His His His Glu Ala Ser Ser Trp Ala Asp Ser Ser Arg His Ser Leu 2210 2215 2220 Val Gly Gln Gly Gln Ser Ser Gly Pro Arg Thr Ser Arg Pro Arg Gly 2225 2230 2235 2240 Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser 2245 2250 2255 Glu Arg Arg Ser Gly Ser Ala Ser Arg Asn His His Gly Ser Ala Gln 2260 2265 2270 Glu Gln Ser Arg Asp Gly Ser Arg His Pro Arg Ser His His Glu Asp 2275 2280 2285 Arg Ala Gly His Gly His Ser Ala Glu Ser Ser Arg Gln Ser Gly Thr 2290 2295 2300 His His Ala Glu Asn Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu 2305 2310 2315 2320 Gln Ala Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Gln 2325 2330 2335 Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 2340 2345 2350 Ser Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln Ala 2355 2360 2365 Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser 2370 2375 2380 Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His Gln Glu Ser Thr 2385 2390 2395 2400 Arg Gly Arg Ser Ala Gly Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr 2405 2410 2415 Gln Val Ser Thr His Glu Gln Ser Glu Ser Ala His Gly Arg Thr Gly 2420 2425 2430 Thr Ser Thr Gly Gly Arg Gln Gly Ser His His Lys Gln Ala Arg Asp 2435 2440 2445 Ser Ser Arg His Ser Thr Ser Gln Glu Gly Gln Asp Thr Ile His Gly 2450 2455 2460 His Pro Gly Ser Ser Ser Gly Gly Arg Gln Gly Ser His Tyr Glu Gln 2465 2470 2475 2480 Leu Val Asp Arg Ser Gly His Ser Gly Ser His His Ser His Thr Thr 2485 2490 2495 Ser Gln Gly Arg Ser Asp Ala Ser His Gly His Ser Gly Ser Arg Ser 2500 2505 2510 Ala Ser Arg Gln Thr Arg Asn Asp Glu Gln Ser Gly Asp Gly Ser Arg 2515 2520 2525 His Ser Gly Ser Arg His His Glu Ala Ser Ser Arg Ala Asp Ser Ser 2530 2535 2540 Gly His Ser Gln Val Gly Gln Gly Gln Ser Glu Gly Pro Arg Thr Ser 2545 2550 2555 2560 Arg Asn Trp Gly Ser Ser Phe Ser Gln Asp Ser Asp Ser Gln Gly His 2565 2570 2575 Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn His His 2580 2585 2590 Gly Ser Ala Gln Glu Gln Leu Arg Asp Gly Ser Arg His Pro Arg Ser 2595 2600 2605 His Gln Glu Asp Arg Ala Gly His Gly His Ser Ala Asp Ser Ser Arg 2610 2615 2620 Gln Ser Gly Thr Arg His Thr Gln Thr Ser Ser Gly Gly Gln Ala Ala 2625 2630 2635 2640 Ser Ser His Glu Gln Ala Arg Ser Ser Ala Gly Glu Arg His Gly Ser 2645 2650 2655 His His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His 2660 2665 2670 Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr Ser 2675 2680 2685 Gly Ser Gln Ala Ser Asp Asn Glu Gly His Ser Glu Asp Ser Asp Thr 2690 2695 2700 Gln Ser Val Ser Ala His Gly Gln Ala Gly Ser His Gln Gln Ser His 2705 2710 2715 2720 Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Thr Ser Gly His Ser Gly 2725 2730 2735 Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Ser His 2740 2745 2750 Gly Trp Thr Gly Pro Ser Thr Arg Gly Arg Gin Gly Ser Arg His Glu 2755 2760 2765 Gln Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln Asp Gly Gln Asp 2770 2775 2780 Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly Tyr 2785 2790 2795 2800 His His Glu His Ser Val Asp Ser Ser Gly His Ser Gly Ser His His 2805 2810 2815 Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser Arg Gly Gln Ser 2820 2825 2830 Gly Ser Arg Ser Ala Ser Arg Thr Thr Arg Asn Glu Glu Gln Ser Gly 2835 2840 2845 Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala Ser Thr His 2850 2855 2860 Ala Asp Ile Ser Arg His Ser Gln Ala Val Gln Gly Gln Ser Glu Gly 2865 2870 2875 2880 Ser Arg Arg Ser Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Ser Asp 2885 2890 2895 Ser Glu Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser 2900 2905 2910 Arg Asn His His Gly Ser Ala Gln Glu Gln Leu Arg Asp Gly Ser Arg 2915 2920 2925 His Pro Arg Ser His Gln Glu Asp Arg Ala Gly His Gly His Ser Ala 2930 2935 2940 Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Gln Thr Ser Ser Gly 2945 2950 2955 2960 Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala Gly Glu 2965 2970 2975 Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser Ser Arg His Ser 2980 2985 2990 Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Gly His 2995 3000 3005 Arg Gly Tyr Ser Gly Ser Gln Ala Ser Asp Asn Glu Gly His Ser Glu 3010 3015 3020 Asp Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Ser His 3025 3030 3035 3040 Gln Gln Ser His Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Thr Ser 3045 3050 3055 Gly His Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser 3060 3065 3070 Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Arg Gly Arg Gln Gly 3075 3080 3085 Ser Arg His Glu Gln Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln 3090 3095 3100 Tyr Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly 3105 3110 3115 3120 Arg Gln Gly Tyr His His Glu His Ser Val Asp Ser Ser Gly His Ser 3125 3130 3135 Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser 3140 3145 3150 Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr Arg Asn Glu 3155 3160 3165 Glu Gln Ser Gly Asp Ser Ser Arg His Ser Val Ser Arg His His Glu 3170 3175 3180 Ala Ser Thr His Ala Asp Ile Ser Arg His Ser Gln Ala Val Gln Gly 3185 3190 3195 3200 Gln Ser Glu Gly Ser Arg Arg Ser Arg Arg Gln Gly Ser Ser Val Ser 3205 3210 3215 Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg Trp Ser 3220 3225 3230 Gly Ser Ala Ser Arg Asn His Arg Gly Ser Val Gln Glu Gln Ser Arg 3235 3240 3245 His Gly Ser Arg His Pro Arg Ser His His Glu Asp Arg Ala Gly His 3250 3255 3260 Gly His Ser Ala Asp Arg Ser Arg Gln Ser Gly Thr Arg His Ala Glu 3265 3270 3275 3280 Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser 3285 3290 3295 Ser Pro Gly Glu Arg His Gly Ser Arg His Gln Gln Ser Ala Asp Ser 3300 3305 3310 Ser Arg His Ser Gly Ile Pro Arg Gly Gln Ala Ser Ser Ala Val Arg 3315 3320 3325 Asp Ser Arg His Trp Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu 3330 3335 3340 Gly His Ser Glu Glu Ser Asp Thr Gln Ser Val Ser Gly His Gly Gln 3345 3350 3355 3360 Ala Gly Pro His Gln Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser 3365 3370 3375 Gly Gly Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr 3380 3385 3390 His Glu Gln Ser Glu Ser Ala His Gly Arg Thr Arg Thr Ser Thr Gly 3395 3400 3405 Arg Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Ser Ser Arg His 3410 3415 3420 Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser 3425 3430 3435 3440 Ser Arg Arg Gly Arg Gln Gly Ser His Tyr Glu Gln Ser Val Asp Arg 3445 3450 3455 Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg 3460 3465 3470 Ser Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln 3475 3480 3485 Thr Arg Asn Asp Glu Gln Ser Gly Asp Gly Ser Arg His Ser Trp Ser 3490 3495 3500 His His His Glu Ala Ser Thr Gln Ala Asp Ser Ser Arg His Ser Gln 3505 3510 3515 3520 Ser Gly Gln Gly Gln Ser Ala Gly Pro Arg Thr Ser Arg Asn Gln Gly 3525 3530 3535 Ser Ser Val Ser Gln Asp Ser Asp Ser Gln Gly His Ser Glu Asp Ser 3540 3545 3550 Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Ala Gln 3555 3560 3565 Glu Gln Ser Arg Asp Gly Ser Arg His Pro Thr Ser His His Glu Asp 3570 3575 3580 Arg Ala Gly His Gly His Ser Ala Glu Ser Ser Arg Gln Ser Gly Thr 3585 3590 3595 3600 His His Ala Glu Asn Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu 3605 3610 3615 Gln Ala Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Gln 3620 3625 3630 Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 3635 3640 3645 Ser Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln Ala 3650 3655 3660 Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser 3665 3670 3675 3680 Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His Gln Glu Ser Thr 3685 3690 3695 Arg Gly Arg Ser Ala Gly Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr 3700 3705 3710 Gln Val Ser Thr His Glu Gln Ser Glu Ser Ala His Gly Arg Ala Gly 3715 3720 3725 Pro Ser Thr Gly Gly Arg Gln Gly Ser Arg His Glu Gln Ala Arg Asp 3730 3735 3740 Ser Ser Arg His Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly 3745 3750 3755 3760 His Pro Gly Ser Arg Arg Gly Gly Arg Gln Gly Ser Tyr His Glu Gln 3765 3770 3775 Ser Val Asp Arg Ser Gly His Ser Gly Ser His His Ser His Thr Thr 3780 3785 3790 Ser Gln Gly Arg Ser Asp Ala Ser His Gly Gln Ser Gly Ser Arg Ser 3795 3800 3805 Ala Ser Arg Glu Thr Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg 3810 3815 3820 His Ser Gly Ser Arg His His Glu Ala Ser Thr Gln Ala Asp Ser Ser 3825 3830 3835 3840 Arg His Ser Gln Ser Gly Gln Gly Glu Ser Ala Gly Ser Arg Arg Ser 3845 3850 3855 Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Ala Tyr 3860 3865 3870 Pro Glu Asp Ser Glu Arg Arg Ser Glu Ser Ala Ser Arg Asn His His 3875 3880 3885 Gly Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His Pro Gly Ser 3890 3895 3900 Ser His Arg Asp Thr Ala Ser His Val Gln Ser Ser Pro Val Gln Ser 3905 3910 3915 3920 Asp Ser Ser Thr Ala Lys Glu His Gly His Phe Ser Ser Leu Ser Gln 3925 3930 3935 Asp Ser Ala Tyr His Ser Gly Ile Gln Ser Arg Gly Ser Pro His Ser 3940 3945 3950 Ser Ser Ser Tyr His Tyr Gln Ser Glu Gly Thr Glu Arg Gln Lys Gly 3955 3960 3965 Gln Ser Gly Leu Val Trp Arg His Gly Ser Tyr Gly Ser Ala Asp Tyr 3970 3975 3980 Asp Tyr Gly Glu Ser Gly Phe Arg His Ser Gln His Gly Ser Val Ser 3985 3990 3995 4000 Tyr Asn Ser Asn Pro Val Val Phe Lys Glu Arg Ser Asp Ile Cys Lys 4005 4010 4015 Ala Ser Ala Phe Gly Lys Asp His Pro Arg Tyr Tyr Ala Thr Tyr Ile 4020 4025 4030 Asn Lys Asp Pro Gly Leu Cys Gly His Ser Ser Asp Ile Ser Lys Gln 4035 4040 4045 Leu Gly Phe Ser Gln Ser Gln Arg Tyr Tyr Tyr Tyr Glu 4050 4055 4060 <210> 4 <211> 454 <212> PRT <213> Homo sapiens <400> 4 Met Phe Leu Ala Gln Arg Ser Leu Cys Ser Leu Ser Gly Arg Ala Lys 1 5 10 15 Phe Leu Lys Thr Ile Ser Ser Ser Lys Ile Leu Gly Phe Ser Thr Ser 20 25 30 Ala Lys Met Ser Leu Lys Phe Thr Asn Ala Lys Arg Ile Glu Gly Leu 35 40 45 Asp Ser Asn Val Trp Ile Glu Phe Thr Lys Leu Ala Ala Asp Pro Ser 50 55 60 Val Val Asn Leu Gly Gln Gly Phe Pro Asp Ile Ser Pro Pro Thr Tyr 65 70 75 80 Val Lys Glu Glu Leu Ser Lys Ile Ala Ala Ile Asp Ser Leu Asn Gln 85 90 95 Tyr Thr Arg Gly Phe Gly His Pro Ser Leu Val Lys Ala Leu Ser Tyr 100 105 110 Leu Tyr Glu Lys Leu Tyr Gln Lys Gln Ile Asp Ser Asn Lys Glu Ile 115 120 125 Leu Val Thr Val Gly Ala Tyr Gly Ser Leu Phe Asn Thr Ile Gln Ala 130 135 140 Leu Ile Asp Glu Gly Asp Glu Val Ile Leu Ile Val Pro Phe Tyr Asp 145 150 155 160 Cys Tyr Glu Pro Met Val Arg Met Ala Gly Ala Thr Pro Val Phe Ile 165 170 175 Pro Leu Arg Ser Lys Pro Val Tyr Gly Lys Arg Trp Ser Ser Ser Asp 180 185 190 Trp Thr Leu Asp Pro Gln Glu Leu Glu Ser Lys Phe Asn Ser Lys Thr 195 200 205 Lys Ala Ile Ile Leu Asn Thr Pro His Asn Pro Leu Gly Lys Val Tyr 210 215 220 Asn Arg Glu Glu Leu Gln Val Ile Ala Asp Leu Cys Ile Lys Tyr Asp 225 230 235 240 Thr Leu Cys Ile Ser Asp Glu Val Tyr Glu Trp Leu Val Tyr Ser Gly 245 250 255 Asn Lys His Leu Lys Ile Ala Thr Phe Pro Gly Met Trp Glu Arg Thr 260 265 270 Ile Thr Ile Gly Ser Ala Gly Lys Thr Phe Ser Val Thr Gly Trp Lys 275 280 285 Leu Gly Trp Ser Ile Gly Pro Asn His Leu Ile Lys His Leu Gln Thr 290 295 300 Val Gln Gln Asn Thr Ile Tyr Thr Cys Ala Thr Pro Leu Gln Glu Ala 305 310 315 320 Leu Ala Gln Ala Phe Trp Ile Asp Ile Lys Arg Met Asp Asp Pro Glu 325 330 335 Cys Tyr Phe Asn Ser Leu Pro Lys Glu Leu Glu Val Lys Arg Asp Arg 340 345 350 Met Val Arg Leu Leu Glu Ser Val Gly Leu Lys Pro Ile Val Pro Asp 355 360 365 Gly Gly Tyr Phe Ile Ile Ala Asp Val Ser Leu Leu Asp Pro Asp Leu 370 375 380 Ser Asp Met Lys Asn Asn Glu Pro Tyr Asp Tyr Lys Phe Val Lys Trp 385 390 395 400 Met Thr Lys His Lys Lys Leu Ser Ala Ile Pro Val Ser Ala Phe Cys 405 410 415 Asn Ser Glu Thr Lys Ser Gin Phe Glu Lys Phe Val Arg Phe Cys Phe 420 425 430 Ile Lys Lys Asp Ser Thr Leu Asp Ala Ala Glu Glu Ile Ile Lys Ala 435 440 445 Trp Ser Val Gln Lys Ser 450

Claims (9)

A composition for prognostic diagnosis of renal cancer according to a tumor type, comprising a reagent capable of detecting a tumor type-specific marker of renal cancer comprising a mutation of the SSC5D gene. The method according to claim 1,
The reagent is a composition comprising one or more selected from the group consisting of primers, probes, aptamers and antibodies. The method according to claim 1,
The tumor type-specific marker is a composition further comprising at least one selected from the group consisting of a mutation of the DDX20 gene, a mutation of the FLG gene, and a mutation of the KYAT3 gene. A kit for prognostic diagnosis of renal cancer according to tumor type, comprising a reagent capable of detecting a tumor type-specific marker of renal cancer containing a mutation in the SSC5D gene. 5. The method according to claim 4,
The reagent is a kit comprising at least one selected from the group consisting of primers, probes, aptamers and antibodies. 5. The method according to claim 4,
The tumor type-specific marker is a kit further comprising at least one selected from the group consisting of a mutation of the DDX20 gene, a mutation of the FLG gene, and a mutation of the KYAT3 gene. preparing sample DNA from a sample of a renal cancer patient;
Using the composition for prognostic diagnosis of any one of claims 1 to 3 or the kit for prognostic diagnosis of renal cancer of any one of claims 4 to 6 for the sample DNA, confirming the presence or absence of a tumor type-specific marker ; A method of providing information necessary for prognostic diagnosis of renal cancer patients, including. 8. The method of claim 7,
A method for providing information necessary for prognostic diagnosis of a renal cancer patient, further comprising amplifying the sample DNA prepared from the renal cancer patient's sample. 8. The method of claim 7,
The method further comprising; determining that the renal cancer patient whose tumor type-specific marker is confirmed has a lower survival rate or a higher recurrence rate than a person whose tumor type-specific marker is not identified.

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