WO2012118856A1 - Gene expression signature in skin predicts response to mycophenolate mofetil - Google Patents

Gene expression signature in skin predicts response to mycophenolate mofetil Download PDF

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WO2012118856A1
WO2012118856A1 PCT/US2012/027020 US2012027020W WO2012118856A1 WO 2012118856 A1 WO2012118856 A1 WO 2012118856A1 US 2012027020 W US2012027020 W US 2012027020W WO 2012118856 A1 WO2012118856 A1 WO 2012118856A1
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ougo
protein
genes
huml
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Michael L. Whitfield
Monique HINCHCLIFF
Chiang-Ching Huang
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Dartmouth College
Northwestern University
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Northwestern University
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/16—Primer sets for multiplex assays

Definitions

  • the present invention is directed generally to methods for identifying mycophenolate mofetil (MMF)-responsive patients diagnosed with systemic sclerosis (SSc)/scleroderma.
  • MMF mycophenolate mofetil
  • SSc systemic sclerosis
  • the invention relates to the identification of gene expression signatures or molecular profiles of skin, which correlate with a SSc/scleroderma patient's responsiveness to treatment with MMF.
  • SSc Systemic sclerosis
  • Scleroderma is a phenotypically diverse autoimmune disease of unknown etiology with a clinical hallmark of skin and internal organ fibrosis. Skin - tightening and internal organ dysfunction cause considerable morbidity and mortality in those with SSc, respectively.
  • Patients are prescribed various experimental treatments, including mycophenolate mofetil (MMF) (e.g., CELLCEPT ® , Roche), an immunosuppressant, to halt and/or reverse skin and lung disease. Response to treatment is variable.
  • MMF mycophenolate mofetil
  • MMF inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes. Inhibition of the enzyme results in alteration of cell-mediated immunity and antibody formation [Ransom, J.T., Therapeutic Drug
  • MMF is a well-tolerated, safe, and FDA-approved medication for the prevention and treatment of solid organ transplant rejection. Its off-label indications include treatment for lupus nephritis, idiopathic thrombocytopenic purpura, Wegener's granulomatosis, myasthenia gravis and psoriasis, which are diseases that are thought to result in part from immune system activation. Because allograft vasculopathy resembles the vasculopathy that occurs in SSc, and because allograft vasculopathy is thought to play a major role in allograft rejection, MMF has been used in transplant recipients and SSc patients.
  • the modified Rodnan Skin Score is a validated marker of skin disease in SSc [Clements, P.J., et al., J Rheumatol, 1993. 20( 1 1 ): p. 1892-6]. Improvement in the score is associated with improved survival. It appears to improve in some patients taking MMF. Lung function and radiographic findings improve in some patients prescribed MMF. Case reports and retrospective studies suggest that MMF may effectively treat SSc skin and lung disease in some patients, but the response is variable and there is no biomarker capable of predicting response to MMF treatment [Plastiras, S.C. et al, Rheumatology, 2006. 45( 12): p.
  • Described herein are methods and compositions for identifying patients with SSc who are likely to respond to MMF treatment.
  • the method is a method of determining if a patient having SSc or scleroderma is a responder to MMF treatment or a non-responder to MMF treatment, comprising obtaining a gene expression signature (patient gene expression signature) from skin obtained from a patient (referred to as a patient to be assessed); and determining if the patient gene expression signature comprises increased expression of one or more (at least one) genes selected from A2M, AEF1 , ALOX5AP, APOL2, APOL3, BATF, BCL3, BERC 1 , BTN3A2, C l Oorfl O, C lorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTL1 , CP A3, CPVL, CTAG 1 B, DDX58, EBI2, EVI2B, F 13A 1 , FAM20A, FAP,
  • 2613340-2 FCGR3A, FUl 1259, FLJ22573, FLJ23221, FLJ25200, FYB, GBPl, GBP3, GEM, GEMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLS1, HLA-DMA, HLA-DOA, HLA-DPA1, HLA- DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB 1, HLA-DRB5, ICAM2, IFI16, EFIT1, EFIT2, EFITM 1 , IFITM2, IFITM3, IL10RA, INDO, ITGB2, KIAA0063, LAMB 1 , LCP1, LGALS2, LGALS9, LILRB2, LOC387763, LOC400759, LUM, LYZ, MARCKS, MFNG, MGC24133, MPEG 1 , MRC1, MRCL3, MS4A6A, MX 1 , NNMT, NUP62, PAG, PLAU
  • the patient gene signature compared to expression of the gene in a control sample, wherein increased expression of one or more of the genes in the patient gene signature classifies the patient as a MMF treatment responder.
  • a patient skin sample used in the method can be referred to as a test genetic sample. If the patient gene signature does not comprise increased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder, as described herein), the patient is classified as a MMF treatment non-responder. Alternatively, the patient gene expression signature can be assessed to determine if it comprises increased expression of one or more (at least one) genes herein as genes within Group III (see below).
  • the method of determining if a patient having SSc or scleroderma is a responder to MMF treatment or a non-responder to MMF treatment comprises obtaining a gene expression signature (patient gene expression signature) from skin obtained from a patient (referred to as a patient to be assessed); and determining if the patient gene expression signature comprises increased expression of one or more (at least one) genes (referred to herein as genes within Group II) selected from the following: genes, identified by name: AADAC, ADAM 17, ADH1A, ADH1C, AHNAK, ALG1, ALG5, AMOT, AOX1, AP2A2, ARK5, ARL6EP5, ARMCX1, BECN1, BECN1, BMP8A, BNIP3L, ClOorfl 19, Clorf24, Clorf37, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2,
  • 2613340-2 KIAA0494, IAA0562, KIAA0870, KIAA1190, KIF25, KLHL18, L 2, LAMP2, LEPROTL1, LHFP, LM02, LOCI 14990, LOC255458, LOC387680, LOC400027,
  • the patient gene signature does not comprise increased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder, as described herein), the patient is classified as a MMF treatment non-responder.
  • the method of determining if a patient having SSc or scleroderma is a responder to MMF treatment or a non-responder to MMF treatment comprises obtaining a gene expression signature (patient gene expression signature) from skin obtained from a patient (referred to as a patient to be assessed); and determining if the patient gene expression signature comprises decreased expression of one or more genes (referred to herein as genes within Group I) selected from the following: genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C 12orfl4, C14orfl31 , CACNG6, CBLL1 , CBX8, CDC7, CDT1 , CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1 , FGF5, FLJ 10902, FLJ 12438, FLJ 12443, FLJ 124
  • XM_210579, XM_303638, and XM_371684 compared to expression of the gene in a control sample, wherein decreased expression of one or more of the genes in the patient gene signature classifies the patient as a MMF treatment responder. If the patient gene signature does not comprise decreased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder), the patient is classified as a MMF treatment non-responder.
  • the method of determining if a patient having SSc or scleroderma is a responder to MMF treatment or a non-responder to MMF treatment comprises obtaining a gene expression signature (patient gene expression signature) from skin obtained from a patient (referred to as a patient to be assessed); and determining if the patient gene expression
  • 2613340-2 signature comprises: (a) increased expression of any one or more genes in Group III and decreased expression of any one or more genes in Group I; (b) increased expression of any one or more genes in Group III and increased expression of any one or more genes in Group II; or increased expression of any one or more genes in Group III, decreased expression of any one or more genes in Group I and increased expression of any one or more genes in Group II.
  • a method of determining if a patient having Systemic Sclerosis (SSc) or scleroderma (referred to as a patient to be assessed) is a responder to mycophenolate mofetil (MMF) treatment or a non-responder to MMF treatment comprises: (a) comparing a gene expression signature obtained from skin of a patient having SSc or scleroderma (patient gene expression signature) to a gene expression signature that is characteristic of a responder to MMF treatment (to a responder gene expression signature) and (b) based on results of comparing in (a), determining if the patient is a responder or a non-responder to MMF treatment.
  • a patient gene expression signature is compared with a responder gene expression signature that comprises increased expression of at least one of the following: A2M, AIFl , ALOX5AP, APOL2, APOL3, BATF, BCL3, BIRC l , BTN3A2, C l Oorfl O, C l orf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTL1 , CPA3, CPVL, CTAG 1 B, DDX58, EBI2, EVI2B, F13A 1 , FAM20A, FAP, FCGR3A, FIJI 1259, FLJ22573, FLJ23221 , FLJ25200, FYB, GBP1 , GBP3, GEM, GEV1AP6, GMFG, GZMH, GZMK, H
  • the patient gene expression signature is compared with a responder gene expression signature that comprises increased expression of one or more (at least one) genes (referred to herein as genes within Group II) selected from the following: genes, identified by name: AADAC, ADAM 17, ADH1A, ADH1C, AHNA , ALG1, ALG5, AMOT, AOX1, AP2A2, ARK5, ARL6IP5, ARMCX1, BECN1, BECN1, BMP8A, BNIP3L, ClOorfl 19, Clorf24, Clorf37, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6, CCNG2, CDC26, CDK2AP1, CDR1, CFHL1, CNTN3, CPNE5, CRTAP, CTNNAl, CTSC, CUTLl, CXCL5, CYBRDl, CYP2R1, D
  • ENST00000305402 ENST00000307901, ENST00000321656, ENST00000322803, ENST00000329246, ENST00000331640, ENST00000332271, ENST00000333784, HI 6080,
  • 2613340-2 L1861543, 1_1882608, 1_1985061, 1_3335767, 1_3551568, 1_3588329, 1_932413, L962800, L966091, NM_001008528, NM_001009555, NM_001013632, NM_001014975,
  • the patient gene signature does not comprise increased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder, as described herein), the patient is classified as a MMF treatment non-responder.
  • the patient gene expression signature is compared with a responder gene expression signature that comprises decreased expression of one or more (at least one) genes (referred to herein as genes within Group I) selected from the following: genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C12orfl4, C14orfl31, CACNG6, CBLL1, CBX8, CDC7, CDT1, CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1, FGF5, FLJ10902, FLJ12438, FLJ12443, FLJ 12484, FLJ 12572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS 3, 1KB KG, IL23A, I SIG1, KIAA1509, KIAA1609, KIAA1666, LDLR
  • a gene expression signature is obtained from a sample, such as a skin sample, obtained from an individual and assessed using methods known to those of skill in the art, as discussed further herein.
  • the skin sample can be obtained from a variety of locations and in some embodiments, is obtained from the arm of the back.
  • nucleic acid (DNA, RNA) microarrays such as a nucleic acid micorarray comprising nucleic acids that hybridize to at least one gene selected from Group III or to a complement of at least one gene selected from Group III, a gene selected from Group II or to a complement thereof, and a gene selected from Group I or to a complement thereof.
  • FIG. 1 shows unsupervised hierarchical clustering analysis of the inflammatory genes that identify the inflammatory intrinsic subset of SSc.
  • FIG. 2A shows differences in gene expression in skin samples excised from the arm between responders and non-responders at baseline as demonstrated by SAM and cluster analysis.
  • FIG. 2B shows differences in gene expression in skin samples excised from the back between responders and non-responders at baseline as demonstrated by SAM and cluster analysis
  • DNA microarrays Gene expression analysis by DNA microarrays is a useful apprroach for identifying novel SSc biomarkers that are capable of meaningfully classifying patients into distinct molecularly defined subsets.
  • DNA microarray analyses of skin may identify useful SSc biomarkers.
  • Published studies have identified SSc gene expression signatures in skin that reliably distinguish patients from healthy individuals and correlate with mRSS [Gardner, H., et al., Arthritis Rheum, 2006. 54(6): p. 1961 -73; Whitfield, M.L., et al., Proc Natl Acad Sci U S A, 2003. 100(21 ): p.
  • Described herein is a method of predicting whether (determining if) a patient with SSc will respond to treatment with MMF, based on assessment of the individual's gene expression signature.
  • MMF responders patients with SSc who are responders to MMF treatment
  • MMF nonresponders patients with SSc who do not respond to MMF treatment
  • the gene expression signature of a patient identified as a MMF treatment responder comprises one or more genes listed in tables and figures included herein.
  • the method comprises comparing a gene expression signature obtained from a sample, such as a skin sample, obtained from a patient having SSc or scleroderma to a gene expression signature standard or reference, and identifying the patient as a responder or non-responder to MMF treatment.
  • a gene expression signature obtained from a sample such as a skin sample
  • a gene expression signature standard or reference e.g., a gene expression signature standard or reference
  • 2613340-2 reference that is one or more (at least one, a) gene (such as a gene set) that differentiates (distinguishes) MMF treatment responders from MMF treatment non-responders.
  • a gene such as a gene set
  • genes whose presence or level or expression in patients with SSc who are known MMF treatment responders can be such a standard.
  • the gene expression signature of a patient with SSc can be compared with the genes listed in Table 1 , Table 1 A, Table 2, Table 3, Table 4 and/or Table 5.
  • the gene expression signature of a patient identified as a responder comprises one or more genes listed in Table 1 , Table 1 A, Table 2, Table 3, Table 4 and/or Table 5 and the difference in expression of the one or more genes between the patient and the standard is statistically significant.
  • the gene expression signature of a patient identified as a responder comprises one or more genes listed in Figure 1 and the difference in expression of the one or more genes between the patient and the standard is statistically significant.
  • the standard genome-wide expression signature is obtained from skin of one or more SSc or scleroderma patient who is not responsive to MMF treatment.
  • the gene expression signature of a patient to be assessed for responsiveness to MMF treatment can be compared with expression of genes in Group I, Group II and/or Group III, as described herein.
  • the gene expression signature of the patient can be assessed for increased expression of one or more genes in Group III, increased expression of one or more genes in Group II, decreased expression of one or more genes in Group I or any combination of the three (e.g., increased expression of one or more genes in Group III and increased expression of one or more genes in Group II).
  • the gene expression signature of a MMF treatment responder comprises at least one gene that categorizes a patient with SSc as in the
  • Inflammatory subtype as defined by Milano, A. et al., PLoS One, 2008. 3(7); p.e2696 and in co-pending US patent application 13/054,244.
  • These include at least one gene named in any of the following: Table 1 , Table 1 A, Table 2, Table 3, Table 4 and Table 5 or otherwise presented herein (Example 4: IL- 13 and IL-4 Gene Signatures Identify the Inflammatory Subset and the tables included therein)
  • a MMF treatment responder can be identified by the increased expression in a sample obtained from a patient with SSc of one or more genes (referred to in US patent application 13/054,244 and herein as genes within Group III) selected from the following: genes identified by name: A2M, AIF 1 , ALOX5AP, APOL2,
  • 2613340-2 APOL3, BATF, BCL3, BIRCl, BTN3A2, ClOorflO, Clorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTLl, CPA3, CPVL, CTAGIB, DDX58, EBI2, EVI2B, F13A1, FAM20A, FAP, FCGR3A, F 11259, FLJ22573, FLJ23221, FLJ25200, FYB, GBP1, GBP3, GEM, GIMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLS1, HLA-DMA, HLA-DOA, HLA-DPAl, HLA-DPBl, HLA-DQAl, HLA-DQA2, HLA-DQBl, HLA-DRBl, HLA-DRB5, ICAM2, IFI16, IFI16, IFIT1, BFIT2, IFITM1, IFITM2, E
  • a MMF treatment responder can be identified by the increased expression in a sample obtained from a patient with SSc of one or more genes (referred to in US patent application 13/054,244 and herein as genes within Group II) selected from the following: genes, identified by name: AADAC, ADAM17, ADH1A, ADH1C, AHNAK, ALG1, ALG5, AMOT, AOX1, AP2A2, ARK5, ARL6IP5, ARMCX1, BECN1, BECN1, BMP8A, BNEP3L, ClOorfl 19, Clorf24, Clorf37, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6, CCNG2, CDC26, CDK2AP1, CDR1, CFHL1, CNTN3, CPNE5, CRTAP, CTNNA1, CTSC, CUTL1, CXCL5, CY
  • a MMF treatment responder can be identified by the decreased expression in a sample obtained from a patient with SSc of one or more genes (referred to in US patent application 13/054,244 and herein as genes within Group I) selected from the following: genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C12orfl4, C14orfl31, CACNG6, CBLLl, CBX8, CDC7, CDTl, CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1, FGF5, FLJ 10902, FLJ 12438, FLJ 12443, FLJ 12484, FIJI 2572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS3, IKBKG, IL23A, INSIG1,
  • 2613340-2 NICNl, NPTX1, OAS3, OGDHL, OPRK1, PCNT2, PDZ 1 , PITPNC 1 , PPFIA4, PREB, PRKY, PSMD11, PSPH, PSPHL, PTP4A3, PXMP2, RAB15, RAD51AP1, RIP, RNF121, RPL41, RPS18, RPS4Y1 , RPS4Y2, S 100P, SORD, SP1, SYMPK, SYT6, TM9SF4, TMOD3, TNFRSF12A, TPRA40, TRIP, TRPM7, TTR, TUBB4, VARS2L, ZNF572, and ZSCAN2 and genes, each identified by GenBank accession number: A_24_BS934268, AB065507, AC007051, AI791206, AK022745, AK022893, AK022997, AK094044, AL391244, AL731541, AL928970, BC010544, BC02
  • a MMF responder can be identified by the increased expression of any one or more genes in Group III and the decreased expression of any one or more genes in Group I in a sample obtained from a patient with SSc; by the increased expression of any one or more genes in Group III and the increased expression of any one or more genes in Group II in a sample obtained from a patient with SSc; by the decreased expression of any one or more genes in Group I and the increased expression of any one or more genes in Group II in a sample obtained from a patient with SSc; or by the increased expression of any one or more genes, in Group III, the decreased expression of any one or more genes in Group I and the increased expression of any one or more genes in Group II in a sample obtained from a patient with SSc.
  • 2613340-2 Changes in gene expression in skin biopsies during treatment appear to occur only in patients who demonstrate clinical improvement, as judged by an improvement in mRSS or by other indicators of organ involvement. Described herein are results of microarray gene expression studies of skin biopsies that support use of molecular signatures in skin as SSc biomarker for clinical response to treatment with MMF. Clinical assessments and skin biopsies were performed on a cohort of SSc patients who were receiving MMF treatment for skin disease before the initiation of therapy and at 6 months and 12 months during (after initiation of) MMF treatment. The study identified a gene expression signature in skin in MMF treatment responders and non-responders at baseline and revealed differences in changes in gene expression that occurred in skin during treatment in responders and non- responders.
  • gene expression signature and “molecular signature,” may be used interchangeably and refer to the expression profile of one or more genes obtained from a skin sample.
  • a “gene” may be a single or double-stranded nucleic acid.
  • a gene is known to one of skill in the art to be a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions, and or other functional sequence regions [Pearson, H., Nature, 2006. 441(7092): p. 398-401].
  • a "responder” is a patient diagnosed with SSc or scleroderma who responds positively to treatment with MMF.
  • a patient experiencing a positive response to treatment with MMF is less symptomatic of SSc or scleroderma as compared to a patient who does not respond positively to treatment with MMF (i.e., a non-responder).
  • Skin biopsies or samples used herein may be obtained from any location on a patient's body.
  • the skin sample is obtained from the arm or back of the patient diagnosed with SSc or scleroderma.
  • a gene expression signature can be obtained using a variety of known approaches. For example, DNA microarray or gene chip (e.g., AFFYMETRIX ® ) analyses may be used to obtain a gene expression signature of a patient. Other genetic profiling techniques known to those of skill in the art may also be used, for example, serial analysis of gene expression (SAGE) or other lab-on-a-chip (LOC) technology.
  • SAGE serial analysis of gene expression
  • LOC lab-on-a-chip
  • test sample containing at least one cell from clinically involved ⁇ i.e., diseased tissue is needed (to obtain a sample of nucleic acid, also referred to as a genetic test sample, to be analyzed).
  • Clinically involved tissue can include skin, esophagus, heart, lungs, kidneys, or synovium, but it is not so limited.
  • the test sample can include skin, esophagus, heart, lungs, kidneys, or synovium, but it is not so limited.
  • 2613340-2 may be obtained using any technique known in the art, including biopsy, blood sample, sample of bodily fluid (e.g., urine, lymph, ascites, sputum, stool, tears, sweat, pus, etc.), surgical excisions needle biopsy, scraping, etc.
  • the test sample is clinically involved skin.
  • a genetic sample or protein sample is obtained from the test sample, using known methods.
  • the genetic sample contains a nucleic acid, such as RNA (e.g., mRNA) and/or DNA.
  • RNA e.g., mRNA
  • DNA DNA
  • mRNA is used in determining the expression of genes of interest.
  • the expression level of a particular gene can be determined by determining the level or presence of the protein encoded by the mRNA.
  • the test sample is preferably a sample representative of the scleroderma tissue as a whole. Multiple samples can be taken from the same tissue in order to obtain a representative sampling of the tissue.
  • RNA, DNA can be obtained from the test sample using any suitable technique known in the art. See, e.g., Ausubel et al. ( 1999) Current Protocols in Molecular Biology (John Wiley & Sons, Inc., New York); Molecular Cloning: A Laboratory Manual ( 1989) 2nd Ed., ed. by Sambrook, Fritsch, and Maniatis (Cold Spring Harbor Laboratory Press); Nucleic Acid Hybridization ( 1984) B. D. Hames & S. J. Higgins eds.
  • the nucleic acid can be purified from whole cells using DNA or RNA purification techniques.
  • the genetic sample can also be amplified using PCR or in vivo techniques requiring subcloning.
  • the genetic sample is obtained by isolating mRNA from the cells of the test sample and creating cRNA as described herein.
  • Genetic samples are typically obtained from an individual (patient) having or suspected of having scleroderma.
  • the individual is a mammal, e.g., a mouse, rat, hamster, rabbit, goat, sheep, cat, dog, pig, horse, cow, non-human primate, or human.
  • the individual is a human.
  • a "patient having scleroderma” has at least one recognized clinical manifestation of scleroderma.
  • a patient having scleroderma has been diagnosed as having scleroderma.
  • Clinical diagnosis of scleroderma is well known in the medical arts.
  • a patient having scleroderma has been diagnosed as having scleroderma on the basis, at least in part, of histological (optionally immunohistological) examination.
  • a "patient suspected of having scleroderma” has at least one clinical sign or symptom that may suggest that the individual has scleroderma.
  • a patient suspected of having scleroderma is suspected to have scleroderma but has not been diagnosed as having scleroderma.
  • a patient suspected of having scleroderma is suspected to have scleroderma, but has not been diagnosed as having scleroderma on the basis, at least in part, of histological (optionally immunohistological) examination.
  • Raynaud's phenomenon is the presenting symptom in 75 percent of human subjects with scleroderma. This well-described- phenomenon is characterized by episodic digital ischemia, clinically manifested by the sequential development of digital blanching, cyanosis, and rubor (redness) of the fingers or toes following cold exposure and subsequent rewarming. In one embodiment, a patient suspected of having scleroderma has Raynaud's phenomenon.
  • a test sample also referred to here as a genetic sample
  • it can be analyzed for the presence, absence, or level of expression of one or more marker genes, e.g., intrinsic genes as disclosed herein.
  • the analysis can be performed using any techniques known in the art including, but not limited to, sequencing, PCR, RT-PCR, quantitative PCR, hybridization techniques, northern blot analysis, microarray technology, DNA microarray technology, etc.
  • the level of expression can be normalized by comparison to the expression of another gene such as a well-known, well-characterized gene or a housekeeping gene.
  • an array is a solid support with peptide or nucleic acid probes attached to the support.
  • Arrays typically include a plurality of different nucleic acid or peptide probes that are coupled to a surface of a substrate in different, known locations.
  • These arrays also described as microarrays or colloquially "chips", have been generally described in the art, (e.g., U.S. Patent Nos. 5, 143,854, 5,445,934, 5,744,305, 5,677, 195, 6,040, 193, 5,424, 186 and Fodor, et al. (1991) Science 251 :767-777).
  • Arrays can be peptides or nucleic acids on beads, gels, polymeric surfaces, fibers such as fiber optics, glass or any other appropriate substrate, see U.S. Patent Nos. 5,770,358, 5,789, 162,
  • Arrays can be packaged in such a manner as to allow for diagnostics or other manipulation of sample in an all inclusive device, see for example, U.S. Patent Nos. 5,856, 174 and 5,922,591.
  • the use and analysis of arrays is routinely practiced in the art and any conventional scanner and software can be employed.
  • the expression data from a particular marker gene or group of marker genes can be analyzed using statistical methods, such as those described herein, to classify or determine the clinical endpoints of scleroderma patients.
  • the expression of one or more marker genes in the patient skin sample is compared to the expression of the one or more marker genes in a control or reference sample.
  • a control or reference sample can be a sample taken from the same patient, such as clinically uninvolved tissue or normal tissue, a sample from a MMF treatment responder, a sample from a MMF treatment nonresponder or a sample from a healthy individual.
  • a control sample can be expression, such as the average expression of a gene of interest from a cohort of healthy individuals.
  • the control or reference can be a predetermined value, such as values obtained for each gene to be assessed (e.g., each intrinsic gene included in Group III, Group II or Group I or presented elsewhere herein) from a population of patients with SSc or scleroderma who are MMF treatment responders or non-responders.
  • a control or reference sample includes a composite of data derived from a plurality of nucleic acid microarray hybridizations representative of the subtype.
  • the control can serve as a baseline (pretreatment) indicator, useful to identify a patient as a MMF treatment responder or a MMF treatment nonresponder and also as values toward which a non-responder patient must move (perhaps through treatment with other medications) in order to become a MMF treatment responder.
  • a control or reference sample includes a composite of data derived from a plurality of nucleic acid microarray hybridizations used to assess gene expression signatures of patients known to respond to MMF treatment, such as microarray hybridizations analyzing MMF treatment responders described herein.
  • a subject having or suspected of having scleroderma can be identified as MMF treatment responsive (or likely to respond to MMF treatment) or MMF treatment non-responsive. That a patient or subject is an MMF treatment responder can be confirmed using additional known methods.
  • the patient can be treated with MMF and the effect on mRSS or other indicators of organ involvement assessed.
  • an improvement in mRSS is an indicator of positive response to MMF treatment.
  • sample classification is performed by Pearson correlations to the average centroid of the genes shown to be up- or down-regulated in each group. Both up- and down-regulated genes can be important. As explained herein, this profile can be measured in skin biopsies of patients with scleroderma using either a gene
  • 2613340-2 expression microarray or, especially for small subsets of genes, by a method such as quantitative PCR.
  • a prospective, open-label, observational study was conducted in a clinically well- characterized cohort of SSc patients who were receiving MMF treatment for progressive skin disease in the opinion of the treating physician.
  • Detailed clinical assessments and skin biopsies were performed before the initiation of therapy and at 6 and 12 months during MMF treatment.
  • the purpose of the study was to identify a gene expression signature in skin in MMF treatment responders (responders) and those who do not respond to MMF treatment (non-responders) at baseline (before MMF treatment) and to analyze the differences in the changes in gene expression that occurred in skin during treatment in responders and non- responders.
  • RNAlater ® Applied Biosystems, Ambion ® , Carlsbad, California, U.S.A.
  • RNA was amplified and labeled using the Agilent Technologies (Santa Clara, California, U.S.A.) low input fluorescent linear amplification for hybridization as described previously [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696]. Briefly, subject RNA was labeled with Cy3 dye, and Universal Human Reference RNA (UHR) (Stratagene) (Agilent Technologies) was labeled with fluorescent Cy5 dye.
  • UHR Universal Human Reference RNA
  • the cRNA was purified and co-hybridized with UHR RNA to whole human genome microarrays, representing 41 ,000 unique probes.
  • the hybridization was carried out for 17 hours at 65°C. A total of 89 arrays were hybridized, which included technical replicates.
  • Arrays were washed and scanned and Gene Pix Pro 5.0 software. Data were Log2 LOWESS normalized for the Cy5/Cy3 ratio, and data was filtered to select array spots with an intensity 2 fold or greater than the local background in either the Cy3 or Cy5 channel. Any probes missing more than 20% of the data across all arrays were omitted from further analysis.
  • Intrinsic gene analysis was conducted as previously described to identify the genes that are most similar between forearm and back samples for a given individual, but most different between individuals [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696].
  • the algorithm calculated the ratio of the variability within each group of arrays to the variability between each group of arrays.
  • the weighted average of the variance of each group of arrays formed the value of the numerator (A).
  • the weighted average of the gene expression for arrays in each group was calculated and the variance of the average gene expression across all groups of arrays formed the denominator (B).
  • the within group variance divided by the between group variance resulted in an "intrinsic score" for each probe.
  • an FDR value the gene expression data was permuted multiple times, and the intrinsic gene algorithm was used with each of the permuted gene expression datasets. The average number of probes that were less than a given intrinsic score cutoff in the permuted data was divided by the number of probes that obtained the intrinsic score cutoff in the non-permuted data. This value was multiplied by 100 to provide a percentage FDR rate.
  • 2613340-2 responders and non-responders, and whether MMF responders cluster in the same molecularly defined subset that have been previously described (Diffuse 1 , Diffuse 2, Inflammatory, Normal-like and Limited) [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696].
  • This analysis identified genes having expression patterns most similar between arm and back biopsies for each subject having the greatest variance among all samples, which has been termed !intrinsic gene analysis' [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696].
  • MMF- responders' baseline gene expression patterns was compared to 6 or 12 month post-MMF treatment levels. Genes having expression that changed concordantly between pre- and post- treatment in arm and back samples were analyzed further. In arm or back samples, 572 genes that had a p ⁇ 0.002 (FDR 10%) were identified (Table 1). See also Table 1 A. There were dramatic differences in gene expression in arm samples between responders and non- responders at baseline as demonstrated by SAM and cluster analysis (FIG. 2A). The difference in back samples was not as clear, suggesting that skin biopsies from the forearm may be more useful in predicting response to MMF in patients with SSc (FIG. 2B).
  • H2A histone family, member Z H2A
  • immunoglobulin domain (Ig) short
  • AKR7A2 A2 (aflatoxin aldehyde reductase) NM_003689 eukaryotic translation initiation factor
  • 2613340-2 Entrez ED Gene Symbol Gene Name Accession subunit 2; translocated to, 2
  • subfamily B member 6 DnaJ (Hsp40)
  • TBC 1 (tre-2 USP6, BUB2, cdc l 6)
  • VPS33B interacting protein VPS33B interacting protein, apical-
  • 2613340-2 Entrez ID Gene Symbol Gene Name Accession ribonucleoprotein, homolog (yeast)
  • MOB 1 Mps One Binder kinase
  • an "intrinsic gene” is a gene that shows little variance within repeated samplings of tissue from an individual subject having scleroderma, but which shows high variance across the same tissue in multiple subjects, wherein the multiple subjects include both subjects having scleroderma and subjects not having scleroderma.
  • an intrinsic gene can be a gene that shows little variance within repeated samplings of forearm- back skin pairs in a subject having scleroderma, but which shows high variance across forearm-back skin pairs of other subjects, wherein the other subjects include both subjects having scleroderma and subjects not having scleroderma.
  • An intrinsic gene set is a group of genes including one or more intrinsic genes.
  • a minimal intrinsic gene set is defined herein as being derived from an intrinsic gene set, and is comprised of the smallest number of intrinsic genes that can be used to classify a sample.
  • intrinsic gene sets were used to classify scleroderma into a Diffuse-Proliferation group or subtype thereof, Inflammatory group, Limited group or Normal-Like group.
  • the Diffuse-Proliferation group is composed solely of patients with a diagnosis of dSSc.
  • the Inflammatory group includes patients with dSSc, ISSc and morphea.
  • the Limited group is composed solely of patients with ISSc.
  • the Normal-Like group includes healthy controls along with dSSc and ISSc patients.
  • the Diffuse-Proliferation group is also defined in part by the general absence of an Inflammatory signature, although there can be some overlap between the Inflammatory and Diffuse-Proliferation signatures.
  • Group I genes include 138 genes, the increased expression of which is indicative of the Diffuse-Proliferation group. Expression of these genes is decreased in the Inflammatory, Limited, and Normal-Like groups. Referring to Table 3 below, included in the genes of Group I are the following genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C12orfl4, C14orfl31, CACNG6, CBLLl, CBX8, CDC7, CDTl, CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1, FGF5, FLJ 10902, FLJ 12438, FLJ 12443, FLJ 12484, FLJ 12572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS3, IKBKG, IL23A, DNSIG1, KI
  • genes of Group I are the following genes, each identified by GenBank accession number only: A_24_BS934268, AB065507, AC007051, AI791206, A 022745, AK022893, A 022997, AK094044, AL391244, AL731541, AL928970, BC010544, BC020847, BM925639, BM928667, ENST00000328708, ENST00000333517, L1891291, 1_3580313, NM_001009569, NM_001024808, NM_172020, NM_173705, NM_178467, NR_001544, THC1434038, THC1484458, THC1504780, U62539,
  • Group II genes include 298 genes, the decreased expression of which is also indicative of the Diffuse- Proliferation group. Expression of these genes is increased in the Inflammatory, Limited, and Normal-Like groups. Referring to Table 3 below, included in the genes of Group II are the following genes, each identified by name: AADAC, ADAM17, ADH1A, ADH1C, AHNA , ALG1, ALG5, AMOT, AOX1, AP2A2, AR 5, ARL6EP5, ARMCX1, BECN1, BECN1, BMP8A, BNIP3L, ClOorfl 19, Clorf24, C lorf37, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6,
  • 2613340-2 CCNG2, CDC26, CDK2AP1, CDRl, CFHLl, CNTN3, CPNE5, CRTAP, CTNNAl, CTSC, CUTL1, CXCL5, CYBRD1, CYP2R1, DBN1, DCAMKL1, DCL-1 , DIAPH2, DK 2, ECHDC3, ECM2, EEF3S7, EMB, EMCN, EMILIN2, ENPP2, EPB41L2, FBLN1, FBLN2, FEM1A, FGL2, FHL5, F BP7, FLU, FU10986, FLJ20032, FLJ20701, FLJ23861,
  • NIPSNAP3B OPTN, OSR2, PAM, PBXIP1, PCOLCE2, PDGFC, PDGFRA, PDGFRL, PEX19, PHAX, PIP, PKM2, PKP2, PMP22, POU2F1, PPAP2B, PRAC, PSMA5,
  • genes of Group II are the following genes, each identified by GenBank accession number only: A_32_BS 169243, A_32_BS200773, A_32_BS53976, AC025463, AF124368, AF161364, AF318337,
  • 2613340-2 THC1531579, THC1544941, THC1551463, THC1559236, THC1560798, THC1563147, THC1572906, THC1574967, THC1591470, XM_165930, and XM_209429.
  • the Inflammatory group is identified by increased expression of a group of 119 genes in Group III. These genes show low expression in the Diffuse-Proliferation, Limited, and Normal-Like groups. Referring to Table 3 below, included in the genes of Group III are the following genes, each identified by name: A2M, ADF1, ALOX5AP, APOL2, APOL3, BATF, BCL3, BIRCl, BTN3A2, ClOorflO, Clorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTLl, CPA3, CPVL, CTAGIB, DDX58, EBI2, EVI2B, F13A1, FAM20A, FAP, FCGR3A, FUl 1259, FLI22573, FLJ23221, FLJ25200, FYB, GBP1, GBP3, GEM, GIMAP6, GMFG, GZMH, GZMK, H
  • genes of Group III are the following genes, each identified by GenBank accession number only: AF533936, BQ049338, ENST00000310210, ENST00000313904, ENST00000329660, 1_1000437, 1_966691, M15073, NM_001010919, NM_001025201, NM_001033569, THC 1543691, and XM_291496.
  • the Inflammatory group and likewise a subject that can be categorized as falling within the Inflammatory group, can be identified by the increased expression of any one or more genes within Group III.
  • the Inflammatory group and likewise a subject that can be categorized as falling within the Inflammatory group, can be identified by the increased expression of any one or more genes within Group III and the decreased expression of any one or more genes in Group I.
  • the Inflammatory group and likewise a subject that can be categorized as falling within the Inflammatory group, can be identified by the increased expression of any one or more genes within Group III and the increased expression of any one or more genes within Group II.
  • the Inflammatory group and likewise a subject that can be categorized as falling within the Inflammatory group, can be identified by the increased expression of any one or more genes within Group III, the decreased expression of any one or more genes in Group I, and the increased expression of any one or more genes within Group II.
  • Beclin 1 (coiled-coil, myosin-like BCL2
  • Beclin 1 (coiled-coil, myosin-like BCL2
  • BMP8A Bone morphogenetic protein 8a AK093659
  • Chromobox homolog 8 (Pc class homolog,
  • CD86 antigen CD28 antigen ligand 2, B7-2
  • CDW52 CDW52 antigen (CAMPATH- I antigen) NM_001803
  • CTAGE4 CTAGE family member 4 XM_496933
  • Catenin cadherin-associated protein
  • alpha 1 alpha 1
  • Cytochrome P450 family 2, subfamily R,
  • Cytochrome P450 family 4, subfamily V,
  • Epstein-Barr virus induced gene 2 (lymphocyte-1)
  • EIF4B Eukaryotic translation initiation factor 4B NM 001417

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Abstract

Described herein are methods and compositions for identifying patients with SSc or scleroderma who are responders to MMF treatment.

Description

GENE EXPRESSION SIGNATURE IN SKIN PREDICTS RESPONSE TO
MYCOPHENOLATE MOFETIL
GOVERNMENT FUNDING
This application was made with government support under Grant No. HD055884, awarded by National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health & Human Development, and under Grant No. AR048098, awarded by NIH. The government has certain rights in the invention
RELATED APPLICATION
This application claims the benefit of the filing date of U.S. provisional application USSN 61/447,545, filed February 28, 201 1. The referenced application is incorporated herein by reference in its entirety.
FIELD
The present invention is directed generally to methods for identifying mycophenolate mofetil (MMF)-responsive patients diagnosed with systemic sclerosis (SSc)/scleroderma. In particular, the invention relates to the identification of gene expression signatures or molecular profiles of skin, which correlate with a SSc/scleroderma patient's responsiveness to treatment with MMF.
BACKGROUND
Systemic sclerosis (SSc)/scleroderma is a phenotypically diverse autoimmune disease of unknown etiology with a clinical hallmark of skin and internal organ fibrosis. Skin - tightening and internal organ dysfunction cause considerable morbidity and mortality in those with SSc, respectively. Patients are prescribed various experimental treatments, including mycophenolate mofetil (MMF) (e.g., CELLCEPT®, Roche), an immunosuppressant, to halt and/or reverse skin and lung disease. Response to treatment is variable.
MMF inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes. Inhibition of the enzyme results in alteration of cell-mediated immunity and antibody formation [Ransom, J.T., Therapeutic Drug
Monitoring, 1995. 17(6): p. 681 -4]. MMF is a well-tolerated, safe, and FDA-approved medication for the prevention and treatment of solid organ transplant rejection. Its off-label indications include treatment for lupus nephritis, idiopathic thrombocytopenic purpura, Wegener's granulomatosis, myasthenia gravis and psoriasis, which are diseases that are thought to result in part from immune system activation. Because allograft vasculopathy resembles the vasculopathy that occurs in SSc, and because allograft vasculopathy is thought to play a major role in allograft rejection, MMF has been used in transplant recipients and SSc patients. Further evidence that supports a role for MMF in the treatment of SSc includes the ability of MMF to inhibit neointimal hyperplasia and prevent collagen production [Roos, N., et al., J Pharmacol Exp Ther, 2007. 321 (2): p. 583-9; Schwarze, M.L., et al., J Heart Lung Transplant, 2001 . 20(2): p. 160].
The modified Rodnan Skin Score (mRSS) is a validated marker of skin disease in SSc [Clements, P.J., et al., J Rheumatol, 1993. 20( 1 1 ): p. 1892-6]. Improvement in the score is associated with improved survival. It appears to improve in some patients taking MMF. Lung function and radiographic findings improve in some patients prescribed MMF. Case reports and retrospective studies suggest that MMF may effectively treat SSc skin and lung disease in some patients, but the response is variable and there is no biomarker capable of predicting response to MMF treatment [Plastiras, S.C. et al, Rheumatology, 2006. 45( 12): p. 1572; Derk, C.T., et al., Rheumatology (Oxford), 2009. 48( 12): p. 1595-9; Gerbino, A.J., et al., Chest, 2008. 133(2): p. 455-60; Herrick, A.L., et al., Journal of Rheumatology, 2010. 37( 1 ): p. 1 16-24; Stratton, R.J., et al., Rheumatology (Oxford), 2001 . 40( 1 ): p. 84-8;
Vanthuyne, M., et al., Clin Exp Rheumatol, 2007. 25(2): p. 287-92; Miniati, I., et al., Clinical and Experimental Rheumatology, 2007. 25(2): p. 169-7 1 ] .
SUMMARY
Described herein are methods and compositions for identifying patients with SSc who are likely to respond to MMF treatment.
In one embodiment, the method is a method of determining if a patient having SSc or scleroderma is a responder to MMF treatment or a non-responder to MMF treatment, comprising obtaining a gene expression signature (patient gene expression signature) from skin obtained from a patient (referred to as a patient to be assessed); and determining if the patient gene expression signature comprises increased expression of one or more (at least one) genes selected from A2M, AEF1 , ALOX5AP, APOL2, APOL3, BATF, BCL3, BERC 1 , BTN3A2, C l Oorfl O, C lorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTL1 , CP A3, CPVL, CTAG 1 B, DDX58, EBI2, EVI2B, F 13A 1 , FAM20A, FAP,
2
2613340-2 FCGR3A, FUl 1259, FLJ22573, FLJ23221, FLJ25200, FYB, GBPl, GBP3, GEM, GEMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLS1, HLA-DMA, HLA-DOA, HLA-DPA1, HLA- DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB 1, HLA-DRB5, ICAM2, IFI16, EFIT1, EFIT2, EFITM 1 , IFITM2, IFITM3, IL10RA, INDO, ITGB2, KIAA0063, LAMB 1 , LCP1, LGALS2, LGALS9, LILRB2, LOC387763, LOC400759, LUM, LYZ, MARCKS, MFNG, MGC24133, MPEG 1 , MRC1, MRCL3, MS4A6A, MX 1 , NNMT, NUP62, PAG, PLAU, PPIC, PTPRC, RAC2, RGS10, RGS16, RSAFDl, SAT, SCGB2A1, SLC20A1, SLC02B1, SPARC, SULF1, TAP1, TCTEL1, TIMP1, TNFSF4, UBD, VSIG4, and
ZFYVE26 compared to expression of the gene in a control sample, wherein increased expression of one or more of the genes in the patient gene signature classifies the patient as a MMF treatment responder. A patient skin sample used in the method can be referred to as a test genetic sample. If the patient gene signature does not comprise increased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder, as described herein), the patient is classified as a MMF treatment non-responder. Alternatively, the patient gene expression signature can be assessed to determine if it comprises increased expression of one or more (at least one) genes herein as genes within Group III (see below).
In an alternative embodiment, the method of determining if a patient having SSc or scleroderma is a responder to MMF treatment or a non-responder to MMF treatment, comprises obtaining a gene expression signature (patient gene expression signature) from skin obtained from a patient (referred to as a patient to be assessed); and determining if the patient gene expression signature comprises increased expression of one or more (at least one) genes (referred to herein as genes within Group II) selected from the following: genes, identified by name: AADAC, ADAM 17, ADH1A, ADH1C, AHNAK, ALG1, ALG5, AMOT, AOX1, AP2A2, ARK5, ARL6EP5, ARMCX1, BECN1, BECN1, BMP8A, BNIP3L, ClOorfl 19, Clorf24, Clorf37, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6, CCNG2, CDC26, CD 2AP1, CDR1, CFHL1, CNTN3, CPNE5, CRTAP, CTNNA1, CTSC, CUTL1, CXCL5, CYBRD1, CYP2R1, DBN1, DCAMKLl, DCL-1, DIAPH2, DKK2, ECHDC3, ECM2, EIF3S7, EMB, EMCN, EMILIN2, ENPP2, EPB41L2, FBLN1, FBLN2, FEM1A, FGL2, FHL5, FKBP7, FLU, FIJI 0986, FLI20032, FLI20701, FLJ23861, FU34969, FLJ36748, FLJ36888, FLJ43339, FZR1, GABPB2, GARNL4, GHITM, GHR, GIT2, GLYAT, GPM6B, GTPBP5, HELB, HOXB4, IFNA6, IGFBP5, IL13RA1, IL15, KAZALD1, KCNK4, KCNS3, KCTD10, KIAA0232,
3
2613340-2 KIAA0494, IAA0562, KIAA0870, KIAA1190, KIF25, KLHL18, L 2, LAMP2, LEPROTL1, LHFP, LM02, LOCI 14990, LOC255458, LOC387680, LOC400027,
LOC493869, LOC87769, LRBA, MAFB, MAGEH1, MAN2B2, MCCC2, MEGF10, MFAP5, MGC11308, MGC15523, MGC3200, MGC35048, MGC45780, MOGAT3, MPPE1, MPZ, MYOIB, MYOC, NFYC, NIPSNAP3B, OPTN, OSR2, PAM, PBXIP1, PCOLCE2, PDGFC, PDGFRA, PDGFRL, PEX19, PHAX, PIP, P M2, PKP2, PMP22, POU2F1, PPAP2B, PRAC, PSMA5, PSORS1C1, PTGIS, RECK, RGS11, RGS5, RIMS3, REPK2, RNASE4, RNF125, RNF13, RNF146, RNF19, ROBOl, ROB03, RPL7A, SARA1, SAV1, SCGB1D1, SDK1, SECP43, SECTM1, SERPINB2, SGCA, SH3BGRL, SH3GLB1, SH3RF2, SLC10A3, SLC12A2, SLC14A1, SLC39A14, SLC7A7, SLC9A9, SLPI, SMAD1, SMAP1, SMARCE1, SMP1, SNTG2, SNX7, SOCS5, SSPN, STX7, SUMF1, TAS2R10, TDE2, TFAP2B, TGFBR2, THSD2, TM4SF3, TMEM25, TMEM34, TNA, TNKS2, TRAD, TRAF3IP1 , TREM4, TRIM35, TRIM9, TTYH2, TUBB1, UBL3, ULK2, URB, USP54, UST, UTRN, UTX, WIF1, WWOX, XG, YPEL5, and ZFHX1B and genes, each identified by GenBank accession number only: A_32_BS 169243, A_32_BS200773, A_32_BS53976, AC025463, AF124368, AF161364, AF318337, AF372624, AK001565, AK022793, AK055621, AK056856, AL050042, AL 137761, BC035102, BC038761 , BC039664, BG252130, BIO 14689, D80006, ENST00000298643, ENST00000300068,
ENST00000305402, ENST00000307901, ENST00000321656, ENST00000322803, ENST00000329246, ENST00000331640, ENST00000332271, ENST00000333784, H16080, 861543, 1_1882608, 1_1985061, 1_3335767, 1_3551568, 1_3588329, 1_932413, 1_962800, L966091, NM_001008528, NM_001009555, NM_001013632, NMJXM014975,
NM_001018006, NM_001018076, NM_001025077, NM_003671, NM_014758,
NM_015262, NM_ 138411, NM_ 153030, NM_ 173709, N _213595, NR_002184, S62210, THC1419743, THC1429821, THC1457118, THC1459712, THC1461073, THC1506312, THC 1511927, THC 1515028, THC 1525318, THC 1531579, THC 1544941 , THC 1551463, THC1559236, THC1560798, THC1563147, THC1572906, THC1574967, THC1591470, XM_ 165930, and XM_209429, compared to expression of the gene in a control sample, wherein increased expression of one or more of the genes in the patient gene signature classifies the patient as a MMF treatment responder. If the patient gene signature does not comprise increased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder, as described herein), the patient is classified as a MMF treatment non-responder.
4
2613340-2 In a further embodiment, the method of determining if a patient having SSc or scleroderma is a responder to MMF treatment or a non-responder to MMF treatment, comprises obtaining a gene expression signature (patient gene expression signature) from skin obtained from a patient (referred to as a patient to be assessed); and determining if the patient gene expression signature comprises decreased expression of one or more genes (referred to herein as genes within Group I) selected from the following: genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C 12orfl4, C14orfl31 , CACNG6, CBLL1 , CBX8, CDC7, CDT1 , CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1 , FGF5, FLJ 10902, FLJ 12438, FLJ 12443, FLJ 12484, F 12572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS 3, 1KB KG, IL23A, INSIG 1 , KIAA 1509, KIAA 1609, KIAA 1666, LDLR, LGALS8, LILRB5, LOC I 23876, LOC I 28977, LOC I 53561 , LOC283464, LRRIQ2, LY6K, MAC30, ME2, MGC13186, MGC 16044, MGC 16075, MGC29784, MGC33839,
MGC35212, MGC4293, MICB, MLL5, MTRF1L, MUC20, NICNl , NPTX 1 , OAS3, OGDHL, OPRK1 , PCNT2, PDZK 1 , PITPNC 1 , PPFIA4, PREB, PRKY, PSMD1 1 , PSPH, PSPHL, PTP4A3, PXMP2, RAB 15, RAD5 1 API , RIP, RNF121 , RPL41 ,. RPS 18, RPS4Y1 , RPS4Y2, S 100P, SORD, SPl , SYMPK, SYT6, TM9SF4, TMOD3, TNFRSF12A, TPRA40, TRIP, TRPM7, TTR, TUBB4, VARS2L, ZNF572, and ZSCAN2 and genes, each identified by GenBank accession number: A_24_BS934268, AB065507, AC007051 , AI791206, AK022745, AK022893, AK022997, AK094044, AL391244, AL731541 , AL928970, BC010544, BC020847, BM925639, BM928667, ENST00000328708, ENST00000333517, L1891291 , 1_3580313, NM_001009569, NM_001024808, NM_172020, NM_173705, NM_178467, NR_001544, THC 1434038, THC 1484458, THC 1504780, U62539,
XM_210579, XM_303638, and XM_371684, compared to expression of the gene in a control sample, wherein decreased expression of one or more of the genes in the patient gene signature classifies the patient as a MMF treatment responder. If the patient gene signature does not comprise decreased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder), the patient is classified as a MMF treatment non-responder.
Alternatively, the method of determining if a patient having SSc or scleroderma is a responder to MMF treatment or a non-responder to MMF treatment, comprises obtaining a gene expression signature (patient gene expression signature) from skin obtained from a patient (referred to as a patient to be assessed); and determining if the patient gene expression
5
2613340-2 signature comprises: (a) increased expression of any one or more genes in Group III and decreased expression of any one or more genes in Group I; (b) increased expression of any one or more genes in Group III and increased expression of any one or more genes in Group II; or increased expression of any one or more genes in Group III, decreased expression of any one or more genes in Group I and increased expression of any one or more genes in Group II.
In a further embodiment of a method of determining if a patient having Systemic Sclerosis (SSc) or scleroderma (referred to as a patient to be assessed) is a responder to mycophenolate mofetil (MMF) treatment or a non-responder to MMF treatment, the method comprises: (a) comparing a gene expression signature obtained from skin of a patient having SSc or scleroderma (patient gene expression signature) to a gene expression signature that is characteristic of a responder to MMF treatment (to a responder gene expression signature) and (b) based on results of comparing in (a), determining if the patient is a responder or a non-responder to MMF treatment. If the patient gene expression signature is sufficiently similar to the responder gene expression signature, the patient to be assessed is a responder to MMF treatment. For example, a patient gene expression signature is compared with a responder gene expression signature that comprises increased expression of at least one of the following: A2M, AIFl , ALOX5AP, APOL2, APOL3, BATF, BCL3, BIRC l , BTN3A2, C l Oorfl O, C l orf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTL1 , CPA3, CPVL, CTAG 1 B, DDX58, EBI2, EVI2B, F13A 1 , FAM20A, FAP, FCGR3A, FIJI 1259, FLJ22573, FLJ23221 , FLJ25200, FYB, GBP1 , GBP3, GEM, GEV1AP6, GMFG, GZMH, GZMK, HAVCR2, HCLS 1 , HLA-DMA, HLA-DOA, HLA-DPA 1 , HLA-DPB 1 , HLA-DQA 1 , HLA-DQA2, HLA-DQB 1 , HLA-DRB 1 , HLA-DRB5, ICAM2, IFI16, ΓΡΠΊ , . IFIT2, ΓΕΙΤΜ Ι , IFITM2, IFITM3, IL 10RA, INDO, ITGB2, KIAA0063, LAMB 1 , LCP 1 , LGALS2, LGALS9, LILRB2, LOC387763, LOC400759, LUM, LYZ, MARCKS, MFNG, MGC24133, MPEG 1 , MRC 1 , MRCL3, MS4A6A, MX 1 , NNMT, NUP62, PAG, PLAU, PPIC, PTPRC, RAC2, RGS 10, RGS 16, RSAFD 1 , SAT, SCGB2A 1 , SLC20A 1 , SLC02B 1 , SPARC, SULF1 , TAP 1 , TCTEL1 , ΤΓ Ρ 1 , TNFSF4, UBD, VSIG4, and ZFYVE26 and, if expression of at least one (one or more) gene(s) in the sample obtained from the patient (in the patient gene expression signature) is substantially the same as expression in the responder gene expression signature (is increased to the same extent or greater extent, compared to expression in a control sample, as the increased expression in the responder gene expression signature), the patient is classified as a MMF responder.
6
2613340-2 Alternatively, the patient gene expression signature is compared with a responder gene expression signature that comprises increased expression of one or more (at least one) genes (referred to herein as genes within Group II) selected from the following: genes, identified by name: AADAC, ADAM 17, ADH1A, ADH1C, AHNA , ALG1, ALG5, AMOT, AOX1, AP2A2, ARK5, ARL6IP5, ARMCX1, BECN1, BECN1, BMP8A, BNIP3L, ClOorfl 19, Clorf24, Clorf37, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6, CCNG2, CDC26, CDK2AP1, CDR1, CFHL1, CNTN3, CPNE5, CRTAP, CTNNAl, CTSC, CUTLl, CXCL5, CYBRDl, CYP2R1, DBNl, DCAMKLl, DCL-1, DIAPH2, DKK2, ECHDC3, ECM2, EIF3S7, EMB, EMCN, EMILIN2, ENPP2, EPB41L2, FBLN1, FBLN2, FEM1A, FGL2, FHL5, FKBP7, FLU, FLJ10986, FLJ20032, FLJ20701, FLJ23861, FLJ34969, FLJ36748, FLJ36888, FLJ43339, FZR1, GABPB2, GARNL4, GHITM, GHR, GIT2, GLYAT, GPM6B, GTPBP5, HELB, HOXB4, IFNA6, IGFBP5, IL13RA1, IL15, KAZALD 1 , KCNK4, KCNS3, KCTD10, KIAA0232, KIAA0494, KIAA0562, KIAA0870, KIAA1190, ΚΓΡ25, KLHL18, KLK2, LAMP2, LEPROTL1, LHFP, LM02, LOCI 14990, LOC255458, LOC387680, LOC400027,
LOC493869, LOC87769, LRBA, MAFB, MAGEH1, MAN2B2, MCCC2, MEGF10, MFAP5, MGC11308, MGC 15523, MGC3200, MGC35048, MGC45780, MOGAT3, MPPE1, MPZ, MYOIB, MYOC, NFYC, NIPSNAP3B, OPTN, OSR2, PAM, ΡΒΧΓΡ1, PCOLCE2, PDGFC, PDGFRA, PDGFRL, PEX19, PHAX, PEP, PKM2, PKP2, PMP22, POU2F1, PPAP2B, PRAC, PSMA5, PSORS1C1, PTGIS, RECK, RGS11, RGS5, REMS3, RBPK2, RNASE4, RNF125, RNF13, RNF146, RNF19, ROBOl, ROB03, RPL7A, SARA1, SAV1, SCGB1D1, SDK1, SECP43, SECTM1, SERPD B2, SGCA, SH3BGRL, SH3GLB1, SH3RF2, SLC10A3, SLC12A2, SLC14A1, SLC39A14, SLC7A7, SLC9A9, SLPI, SMAD1, SMAP1, SMARCE1, SMP1, SNTG2, SNX7, SOCS5, SSPN, STX7, SUMF1, TAS2R10, TDE2, TFAP2B, TGFBR2, THSD2, TM4SF3, TMEM25, TMEM34, TNA, TNKS2, TRAD, TRAF3IP1, TREM4, TREM35, TREM9, TTYH2, TUBB1, UBL3, ULK2, URB, USP54, UST, UTRN, UTX, WEFl, WWOX, XG, YPEL5, and ZFHX1B and genes, each identified by GenBank accession number: A_32_BS 169243, A_32_BS200773, A_32_BS53976, AC025463, AF124368, AF161364, AF318337, AF372624, AK001565, AK022793, AK055621, AK056856, AL050042, AL 137761, BC035102, BC038761, BC039664, BG252130, BI014689, D80006, ENST00000298643, ENST00000300068,
ENST00000305402, ENST00000307901, ENST00000321656, ENST00000322803, ENST00000329246, ENST00000331640, ENST00000332271, ENST00000333784, HI 6080,
7
2613340-2 L1861543, 1_1882608, 1_1985061, 1_3335767, 1_3551568, 1_3588329, 1_932413, L962800, L966091, NM_001008528, NM_001009555, NM_001013632, NM_001014975,
NM_001018006, NM_001.018076, NM_001025077, NM_003671, NM_014758,
NM_015262, M_ 138411, NM_ 153030, NM_173709, N _213595, NR_002184, S62210, THC1419743, THC1429821, THC1457118, THC1459712, THC1461073, THC1506312, THC1511927, THC1515028, THC 1525318, THC 1531579, THC 1544941, THC 1551463, THC1559236, THC1560798, THC1563147, THC1572906, THC1574967, THC1591470, XM_165930, and XM_209429, compared to expression of the gene in a control sample, wherein increased expression of one or more of the genes in the patient gene signature classifies the patient as a MMF treatment responder. If the patient gene signature does not comprise increased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder, as described herein), the patient is classified as a MMF treatment non-responder.
Alternatively, the patient gene expression signature is compared with a responder gene expression signature that comprises decreased expression of one or more (at least one) genes (referred to herein as genes within Group I) selected from the following: genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C12orfl4, C14orfl31, CACNG6, CBLL1, CBX8, CDC7, CDT1, CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1, FGF5, FLJ10902, FLJ12438, FLJ12443, FLJ 12484, FLJ 12572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS 3, 1KB KG, IL23A, I SIG1, KIAA1509, KIAA1609, KIAA1666, LDLR, LGALS8, LILRB5, LOCI 23876, LOC 128977, LOCI 53561, LOC283464, LRRIQ2, LY6K, MAC30, ME2, MGC13186, MGC 16044, MGC 16075, MGC29784, MGC33839,
MGC35212, MGC4293, MICB, MLL5, MTRF1L, MUC20, NICNl, NPTX1, OAS3, OGDHL, OPRK1, PCNT2, PDZK1, PITPNC1, PPFIA4, PREB, PRKY, PSMD11, PSPH, PSPHL, PTP4A3, PXMP2, RAB15, RAD51AP1, REP, RNF121, RPL41, RPS18, RPS4Y1, RPS4Y2, S100P, SORD, SPl, SYMPK, SYT6, TM9SF4, TMOD3, TNFRSF12A, TPRA40, TRIP, TRPM7, TTR, TUBB4, VARS2L, Z F572, and ZSCAN2 and. genes, each identified by GenBank accession number: A_24_BS934268, AB065507, AC007051, AI791206, AK022745, AK022893, AK022997, AK094044, AL391244, AL731541, AL928970, BC010544, BC020847, BM925639, BM928667, ENST00000328708, ENST00000333517, L1891291, L3580313, NM_001009569, NM_001024808, NM_172020, NMJ73705, NM_178467, NR_001544, THC1434038, THC1484458, THC1504780, U62539,
8
2613340-2 XM_210579, XM_303638, and XM_371684, , compared to expression of the gene in a control sample, wherein decreased expression of one or more of the genes in the patient gene signature classifies the patient as a MMF treatment responder. If the patient gene signature does not comprise decreased expression of one or more (at least one) genes from the group above (does not have a gene expression signature indicative of being a MMF treatment responder, as described herein), the patient is classified as a MMF treatment non-responder.
In all embodiments of the method described herein, a gene expression signature is obtained from a sample, such as a skin sample, obtained from an individual and assessed using methods known to those of skill in the art, as discussed further herein. The skin sample can be obtained from a variety of locations and in some embodiments, is obtained from the arm of the back.
Also described herein are nucleic acid (DNA, RNA) microarrays, such as a nucleic acid micorarray comprising nucleic acids that hybridize to at least one gene selected from Group III or to a complement of at least one gene selected from Group III, a gene selected from Group II or to a complement thereof, and a gene selected from Group I or to a complement thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
The patent or patent application contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
FIG. 1 shows unsupervised hierarchical clustering analysis of the inflammatory genes that identify the inflammatory intrinsic subset of SSc.
FIG. 2A shows differences in gene expression in skin samples excised from the arm between responders and non-responders at baseline as demonstrated by SAM and cluster analysis.
FIG. 2B shows differences in gene expression in skin samples excised from the back between responders and non-responders at baseline as demonstrated by SAM and cluster analysis
9
2613340-2 DETAILED DESCRIPTION
Gene expression analysis by DNA microarrays is a useful apprroach for identifying novel SSc biomarkers that are capable of meaningfully classifying patients into distinct molecularly defined subsets. A growing body of evidence suggests that DNA microarray analyses of skin may identify useful SSc biomarkers. Published studies have identified SSc gene expression signatures in skin that reliably distinguish patients from healthy individuals and correlate with mRSS [Gardner, H., et al., Arthritis Rheum, 2006. 54(6): p. 1961 -73; Whitfield, M.L., et al., Proc Natl Acad Sci U S A, 2003. 100(21 ): p. 12319-24; Miiano, A., et al., PLoS One, 2008. 3(7): p. e2696; Sargent, J.L., et al., Curr Rheumatol Rep, 2008. 10(3): p. 205- 1 1] Pendergrass, S.A. et al., J. Invest. Derm. 2012 Feb 9. Gene expression in skin of patients with SSc has been used by Applicant to identify five molecular subsets of the condition (Diffuse 1 , Diffuse 2, Inflammatory, Normal-like and Limited) that help to explain the observed heterogeneity in disease course and response to experimental treatments
[Miiano, A., et al., PLoS One, 2008. 3(7): p. e2696]. A recent study that assessed clinical response to rituximab in SSc patients found no clinical benefit and a lack of significant changes in gene expression in skin biopsies. Pendergrass, S.A. et al., J. Invest. Derm. 2012 Feb 9. These findings contrast with the results of a small study that reported clinical improvement in skin and lung disease in two patients treated with 6 months of imatinib mesylate (e.g., GLEEVEC®, Novartis). Another experimental treatment for SSc identified biologically relevant changes in skin gene expression that coincided with improvement in lung and skin disease [Chung, L., et al., Arthritis Rheum, 2009. 60(2): p. 584-91].
Described herein is a method of predicting whether (determining if) a patient with SSc will respond to treatment with MMF, based on assessment of the individual's gene expression signature. As described herein, Applicant has shown that patients with SSc who are responders to MMF treatment (MMF responders) have a gene expression signature that distinguishes them from patients with SSc who do not respond to MMF treatment (MMF nonresponders). The gene expression signature of a patient identified as a MMF treatment responder comprises one or more genes listed in tables and figures included herein. The method comprises comparing a gene expression signature obtained from a sample, such as a skin sample, obtained from a patient having SSc or scleroderma to a gene expression signature standard or reference, and identifying the patient as a responder or non-responder to MMF treatment. In specific embodiments, the gene expression signature obtained from a sample, such as a skin sample, is compared with a gene expression signature standard or
10
2613340-2 reference that is one or more (at least one, a) gene (such as a gene set) that differentiates (distinguishes) MMF treatment responders from MMF treatment non-responders. For example, one or more genes whose presence or level or expression in patients with SSc who are known MMF treatment responders can be such a standard. For example, the gene expression signature of a patient with SSc can be compared with the genes listed in Table 1 , Table 1 A, Table 2, Table 3, Table 4 and/or Table 5. For example, the gene expression signature of a patient identified as a responder comprises one or more genes listed in Table 1 , Table 1 A, Table 2, Table 3, Table 4 and/or Table 5 and the difference in expression of the one or more genes between the patient and the standard is statistically significant. In a further embodiment, the gene expression signature of a patient identified as a responder comprises one or more genes listed in Figure 1 and the difference in expression of the one or more genes between the patient and the standard is statistically significant.
In another embodiment, the standard genome-wide expression signature is obtained from skin of one or more SSc or scleroderma patient who is not responsive to MMF treatment.
Alternatively, the gene expression signature of a patient to be assessed for responsiveness to MMF treatment can be compared with expression of genes in Group I, Group II and/or Group III, as described herein. For example, the gene expression signature of the patient can be assessed for increased expression of one or more genes in Group III, increased expression of one or more genes in Group II, decreased expression of one or more genes in Group I or any combination of the three (e.g., increased expression of one or more genes in Group III and increased expression of one or more genes in Group II).
In specific embodiments, the gene expression signature of a MMF treatment responder comprises at least one gene that categorizes a patient with SSc as in the
Inflammatory subtype, as defined by Milano, A. et al., PLoS One, 2008. 3(7); p.e2696 and in co-pending US patent application 13/054,244. These include at least one gene named in any of the following: Table 1 , Table 1 A, Table 2, Table 3, Table 4 and Table 5 or otherwise presented herein (Example 4: IL- 13 and IL-4 Gene Signatures Identify the Inflammatory Subset and the tables included therein)
In specific embodiments, a MMF treatment responder can be identified by the increased expression in a sample obtained from a patient with SSc of one or more genes (referred to in US patent application 13/054,244 and herein as genes within Group III) selected from the following: genes identified by name: A2M, AIF 1 , ALOX5AP, APOL2,
2613340-2 APOL3, BATF, BCL3, BIRCl, BTN3A2, ClOorflO, Clorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTLl, CPA3, CPVL, CTAGIB, DDX58, EBI2, EVI2B, F13A1, FAM20A, FAP, FCGR3A, F 11259, FLJ22573, FLJ23221, FLJ25200, FYB, GBP1, GBP3, GEM, GIMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLS1, HLA-DMA, HLA-DOA, HLA-DPAl, HLA-DPBl, HLA-DQAl, HLA-DQA2, HLA-DQBl, HLA-DRBl, HLA-DRB5, ICAM2, IFI16, IFI16, IFIT1, BFIT2, IFITM1, IFITM2, EFITM3, IL10RA, INDO, ITGB2, IAA0063, LAMB 1 , LCP1, LGALS2, LGALS9, LILRB2, LOC387763, LOC400759, LUM, LYZ, MARC S, MFNG, MGC24133, MPEG1, MRC1, MRCL3, MS4A6A, MX1, NNMT, NUP62, PAG, PLAU, PPIC, PPIC, PTPRC, RAC2, RGS10, RGS16, RSAFD1, SAT, SCGB2A1, SLC20A1, SLC02B1, SPARC, SULF1, TAP1, TCTEL1, TEMPI, TNFSF4, UBD, VSIG4, and ZFYVE26 and genes, each identified by GenBank accession number: AF533936, BQ049338, ENST00000310210,
ENST00000313904, ENST00000329660, 1_1000437, 1_966691, M15073, NM_001010919, NM_001025201, NM_001033569, THC1543691, and XM_291496.
In further specific embodiments, a MMF treatment responder can be identified by the increased expression in a sample obtained from a patient with SSc of one or more genes (referred to in US patent application 13/054,244 and herein as genes within Group II) selected from the following: genes, identified by name: AADAC, ADAM17, ADH1A, ADH1C, AHNAK, ALG1, ALG5, AMOT, AOX1, AP2A2, ARK5, ARL6IP5, ARMCX1, BECN1, BECN1, BMP8A, BNEP3L, ClOorfl 19, Clorf24, Clorf37, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6, CCNG2, CDC26, CDK2AP1, CDR1, CFHL1, CNTN3, CPNE5, CRTAP, CTNNA1, CTSC, CUTL1, CXCL5, CYBRD1, CYP2R1, DBN1, DCAM L1, DCL-1, DIAPH2, DKK2, ECHDC3, ECM2, EIF3S7, EMB, EMCN, EMILIN2, ENPP2, EPB41L2, FBLN1, FBLN2, FEM1 A, FGL2, FHL5, FKBP7, FLU, FLJ10986, FLJ20032, FLI20701, FLJ23861, FLJ34969, FLJ36748, FLJ36888, FLJ43339, FZR1, GABPB2, GARNL4, GHITM, GHR, GIT2, GLYAT, GPM6B, GTPBP5, HELB, HOXB4, EFNA6, IGFBP5, IL13RA1, EL 15, KAZALDl, KCNK4, KCNS3, KCTD10, KIAA0232, KIAA0494, KIAA0562, KIAA0870, KIAA1190, KEF25, KLHL18, KLK2, LAMP2, LEPROTL1, LHFP, LM02, LOCI 14990, LOC255458, LOC387680, LOC400027, LOC493869, LOC87769, LRBA, MAFB, MAGEH1, MAN2B2, MCCC2, MEGFIO, MFAP5, MGCl 1308, MGC15523, MGC3200, MGC35048, MGC45780, MOGAT3, MPPE1, MPZ, MYOIB, MYOC, NFYC, NIPSNAP3B, OPTN, OSR2, PAM, ΡΒΧΓ 1, PCOLCE2, PDGFC, PDGFRA, PDGFRL, PEX19, PHAX, PEP, PKM2, PKP2,
12
2613340-2 PMP22, POU2F1, PPAP2B, PRAC, PSMA5, PSORS1C1, PTGIS, RECK, RGS11, RGS5, R S3, RIPK2, RNASE4, RNF125, RNF13, RNF146, RNF19, ROBOl, ROB03, RPL7A, SARA1, SAV1, SCGB1D1, SDK1, SECP43, SECTM1, SERPINB2, SGCA, SH3BGRL, SH3GLB1, SH3RF2, SLC10A3, SLC12A2, SLC14A1, SLC39A14, SLC7A7, SLC9A9, SLPI, SMAD1, SMAP1, SMARCE1, SMP1, SNTG2, SNX7, SOCS5, SSPN, STX7, SUMF1, TAS2R10, TDE2, TFAP2B, TGFBR2, THSD2, TM4SF3, TMEM25, TMEM34, TNA, TNKS2, TRAD, TRAF3IP1, TREM4, TRIM35, TRIM9, TTYH2, TUBB1, UBL3, ULK2, URB, USP54, UST, UTRN, UTX, WIFl, WWOX, XG, YPEL5, and ZFHX1B and genes, each identified by GenBank accession number only: A_32_BS 169243,
A_32_BS200773, A_32_BS53976, AC025463, AF124368, AF161364, AF318337,
AF372624, AK001565, AK022793, AK055621, AK056856, AL050042, AL137761, BC035102, BC038761, BC039664, BG252130, BI014689, D80006, ENST00000298643, ENST00000300068, ENST00000305402, ENST00000307901, ENST00000321656, ENST00000322803, ENST00000329246, ENST00000331640, ENST00000332271, ENST00000333784, H16080, 1_1861543, 1_1882608, 1_1985061, 1_3335767, 1_3551568, L3588329, 1_932413, 1_962800, 1_966091, NM_001008528, NM_001009555,
NM_001013632, NM_001014975, NM_001018006, NM_001018076, NM_001025077, NM_003671, NM_014758, NM_015262, NM_138411, NM_153030, NM_173709,
NM_213595, NR_002184, S62210, THC 1419743, THC 1429821, THC 1457118,
THC 1459712, THC 1461073, THC 1506312, THC1511927, THC 1515028, THC 1525318, THC1531579, THC1544941, THC1551463, THC1559236, THC1560798, THC1563147, THC1572906, THC1574967, THC1591470, XM_165930, and XM_209429.
In further specific embodiments, a MMF treatment responder can be identified by the decreased expression in a sample obtained from a patient with SSc of one or more genes (referred to in US patent application 13/054,244 and herein as genes within Group I) selected from the following: genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C12orfl4, C14orfl31, CACNG6, CBLLl, CBX8, CDC7, CDTl, CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1, FGF5, FLJ 10902, FLJ 12438, FLJ 12443, FLJ 12484, FIJI 2572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS3, IKBKG, IL23A, INSIG1, KIAA1509, KIAA1609, KIAA1666, LDLR, LGALS8, LILRB5, LOC123876, LOC128977, LOC153561, LOC283464, LRRIQ2, LY6K, MAC30, ME2, MGC13186, MGC 16044, MGC 16075, MGC29784, MGC33839, MGC35212, MGC4293, MICB, MLL5, MTRF1L, MUC20,
13
2613340-2 NICNl, NPTX1, OAS3, OGDHL, OPRK1, PCNT2, PDZ 1 , PITPNC 1 , PPFIA4, PREB, PRKY, PSMD11, PSPH, PSPHL, PTP4A3, PXMP2, RAB15, RAD51AP1, RIP, RNF121, RPL41, RPS18, RPS4Y1 , RPS4Y2, S 100P, SORD, SP1, SYMPK, SYT6, TM9SF4, TMOD3, TNFRSF12A, TPRA40, TRIP, TRPM7, TTR, TUBB4, VARS2L, ZNF572, and ZSCAN2 and genes, each identified by GenBank accession number: A_24_BS934268, AB065507, AC007051, AI791206, AK022745, AK022893, AK022997, AK094044, AL391244, AL731541, AL928970, BC010544, BC020847, BM925639, BM928667, ENST00000328708, ENST00000333517, 1_l 891291, 1_3580313, N _001009569,
NM_001024808, N _172020, NM_173705, NM_178467, NR_001544, THC1434038, THC 1484458, THC 1504780, U62539, XM_210579, XM_303638, and XM_371684.
In one embodiment, increased expression of one or more genes selected from A2M, AIF1, ALOX5AP, APOL2, APOL3, BATF, BCL3, BIRCl, BTN3A2, ClOorflO, Clorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTL1, CPA3, CPVL,
CTAG1B, DDX58, EBI2, EVI2B, F13A1, FAM20A, FAP, FCGR3A, FLJ11259, FLJ22573, FLJ23221, FLJ25200, FYB, GBP1, GBP3, GEM, GEMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLS1, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA 1 , HLA- DQA2, HLA-DQB 1 , HLA-DRB 1 , HLA-DRB5, ICAM2, IFI16, IFIT1, IFIT2, EFITM 1 , IFITM2, IFITM3, ILIORA, ENDO, ITGB2, KIAA0063, LAMBl, LCPl, LGALS2, LGALS9, LELRB2, LOC387763, LOC400759, LUM, LYZ, MARCKS, MFNG, MGC24133, MPEG1, MRC1, MRCL3, MS4A6A, MX1, NNMT, NUP62, PAG, PLAU, PPIC, PTPRC, RAC2, RGS10, RGS16, RSAFDl, SAT, SCGB2A1, SLC20A1, SLC02B1, SPARC, SULFl, TAPl, TCTEL1, ΤΓΜΡ1, TNFSF4, UBD, VSIG4, and ZFYVE26 in the test genetic sample compared to the expression in a control sample classifies the patient as a MMF responder.
In further embodiments, a MMF responder can be identified by the increased expression of any one or more genes in Group III and the decreased expression of any one or more genes in Group I in a sample obtained from a patient with SSc; by the increased expression of any one or more genes in Group III and the increased expression of any one or more genes in Group II in a sample obtained from a patient with SSc; by the decreased expression of any one or more genes in Group I and the increased expression of any one or more genes in Group II in a sample obtained from a patient with SSc; or by the increased expression of any one or more genes, in Group III, the decreased expression of any one or more genes in Group I and the increased expression of any one or more genes in Group II in a sample obtained from a patient with SSc.
14
2613340-2 Changes in gene expression in skin biopsies during treatment appear to occur only in patients who demonstrate clinical improvement, as judged by an improvement in mRSS or by other indicators of organ involvement. Described herein are results of microarray gene expression studies of skin biopsies that support use of molecular signatures in skin as SSc biomarker for clinical response to treatment with MMF. Clinical assessments and skin biopsies were performed on a cohort of SSc patients who were receiving MMF treatment for skin disease before the initiation of therapy and at 6 months and 12 months during (after initiation of) MMF treatment. The study identified a gene expression signature in skin in MMF treatment responders and non-responders at baseline and revealed differences in changes in gene expression that occurred in skin during treatment in responders and non- responders.
The terms "gene expression signature" and "molecular signature," may be used interchangeably and refer to the expression profile of one or more genes obtained from a skin sample. A "gene" may be a single or double-stranded nucleic acid. A gene is known to one of skill in the art to be a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions, and or other functional sequence regions [Pearson, H., Nature, 2006. 441(7092): p. 398-401].
A "responder" is a patient diagnosed with SSc or scleroderma who responds positively to treatment with MMF. A patient experiencing a positive response to treatment with MMF is less symptomatic of SSc or scleroderma as compared to a patient who does not respond positively to treatment with MMF (i.e., a non-responder).
Skin biopsies or samples used herein may be obtained from any location on a patient's body. Preferably, the skin sample is obtained from the arm or back of the patient diagnosed with SSc or scleroderma.
A gene expression signature can be obtained using a variety of known approaches. For example, DNA microarray or gene chip (e.g., AFFYMETRIX®) analyses may be used to obtain a gene expression signature of a patient. Other genetic profiling techniques known to those of skill in the art may also be used, for example, serial analysis of gene expression (SAGE) or other lab-on-a-chip (LOC) technology.
.To obtain a gene expression signature, a test sample containing at least one cell from clinically involved {i.e., diseased) tissue is needed (to obtain a sample of nucleic acid, also referred to as a genetic test sample, to be analyzed). Clinically involved tissue can include skin, esophagus, heart, lungs, kidneys, or synovium, but it is not so limited. The test sample
15
2613340-2 may be obtained using any technique known in the art, including biopsy, blood sample, sample of bodily fluid (e.g., urine, lymph, ascites, sputum, stool, tears, sweat, pus, etc.), surgical excisions needle biopsy, scraping, etc. In particular embodiments, the test sample is clinically involved skin. A genetic sample or protein sample is obtained from the test sample, using known methods. The genetic sample contains a nucleic acid, such as RNA (e.g., mRNA) and/or DNA. For example, in determining gene expression, one can obtain mRNA from the test sample and the mRNA may be reverse transcribed into cDNA for further analysis. In another embodiment, mRNA is used in determining the expression of genes of interest. In some embodiments, the expression level of a particular gene can be determined by determining the level or presence of the protein encoded by the mRNA.
The test sample is preferably a sample representative of the scleroderma tissue as a whole. Multiple samples can be taken from the same tissue in order to obtain a representative sampling of the tissue.
A sample containing genetic material (RNA, DNA) can be obtained from the test sample using any suitable technique known in the art. See, e.g., Ausubel et al. ( 1999) Current Protocols in Molecular Biology (John Wiley & Sons, Inc., New York); Molecular Cloning: A Laboratory Manual ( 1989) 2nd Ed., ed. by Sambrook, Fritsch, and Maniatis (Cold Spring Harbor Laboratory Press); Nucleic Acid Hybridization ( 1984) B. D. Hames & S. J. Higgins eds. The nucleic acid can be purified from whole cells using DNA or RNA purification techniques. The genetic sample can also be amplified using PCR or in vivo techniques requiring subcloning. In a particular embodiment, the genetic sample is obtained by isolating mRNA from the cells of the test sample and creating cRNA as described herein.
Genetic samples are typically obtained from an individual (patient) having or suspected of having scleroderma. The individual is a mammal, e.g., a mouse, rat, hamster, rabbit, goat, sheep, cat, dog, pig, horse, cow, non-human primate, or human. In specific embodiments, the individual is a human.
As used herein, a "patient having scleroderma" has at least one recognized clinical manifestation of scleroderma. In one embodiment, a patient having scleroderma has been diagnosed as having scleroderma. Clinical diagnosis of scleroderma is well known in the medical arts. In one embodiment a patient having scleroderma has been diagnosed as having scleroderma on the basis, at least in part, of histological (optionally immunohistological) examination.
16
2613340-2 As used herein, a "patient suspected of having scleroderma" has at least one clinical sign or symptom that may suggest that the individual has scleroderma. In one embodiment a patient suspected of having scleroderma is suspected to have scleroderma but has not been diagnosed as having scleroderma. In one embodiment a patient suspected of having scleroderma is suspected to have scleroderma, but has not been diagnosed as having scleroderma on the basis, at least in part, of histological (optionally immunohistological) examination.
Raynaud's phenomenon is the presenting symptom in 75 percent of human subjects with scleroderma. This well-described- phenomenon is characterized by episodic digital ischemia, clinically manifested by the sequential development of digital blanching, cyanosis, and rubor (redness) of the fingers or toes following cold exposure and subsequent rewarming. In one embodiment, a patient suspected of having scleroderma has Raynaud's phenomenon.
Once a test sample (also referred to here as a genetic sample) has been obtained, it can be analyzed for the presence, absence, or level of expression of one or more marker genes, e.g., intrinsic genes as disclosed herein. The analysis can be performed using any techniques known in the art including, but not limited to, sequencing, PCR, RT-PCR, quantitative PCR, hybridization techniques, northern blot analysis, microarray technology, DNA microarray technology, etc. In determining the expression level of a biomarker gene or genes in a genetic sample, the level of expression can be normalized by comparison to the expression of another gene such as a well-known, well-characterized gene or a housekeeping gene.
In particular embodiments, expression of a marker gene of interest is determined using microarray technology. Generally, an array is a solid support with peptide or nucleic acid probes attached to the support. Arrays typically include a plurality of different nucleic acid or peptide probes that are coupled to a surface of a substrate in different, known locations. These arrays, also described as microarrays or colloquially "chips", have been generally described in the art, (e.g., U.S. Patent Nos. 5, 143,854, 5,445,934, 5,744,305, 5,677, 195, 6,040, 193, 5,424, 186 and Fodor, et al. (1991) Science 251 :767-777). Arrays can be peptides or nucleic acids on beads, gels, polymeric surfaces, fibers such as fiber optics, glass or any other appropriate substrate, see U.S. Patent Nos. 5,770,358, 5,789, 162,
5,708, 153, 6,040, 193 and 5,800,992. Arrays can be packaged in such a manner as to allow for diagnostics or other manipulation of sample in an all inclusive device, see for example, U.S. Patent Nos. 5,856, 174 and 5,922,591. The use and analysis of arrays is routinely practiced in the art and any conventional scanner and software can be employed.
17
2613340-2 The expression data from a particular marker gene or group of marker genes can be analyzed using statistical methods, such as those described herein, to classify or determine the clinical endpoints of scleroderma patients. In this analysis, the expression of one or more marker genes in the patient skin sample is compared to the expression of the one or more marker genes in a control or reference sample. A control or reference sample can be a sample taken from the same patient, such as clinically uninvolved tissue or normal tissue, a sample from a MMF treatment responder, a sample from a MMF treatment nonresponder or a sample from a healthy individual. In addition, a control sample can be expression, such as the average expression of a gene of interest from a cohort of healthy individuals. The control or reference can be a predetermined value, such as values obtained for each gene to be assessed (e.g., each intrinsic gene included in Group III, Group II or Group I or presented elsewhere herein) from a population of patients with SSc or scleroderma who are MMF treatment responders or non-responders.
In one embodiment, a control or reference sample includes a composite of data derived from a plurality of nucleic acid microarray hybridizations representative of the subtype. In this case, the control can serve as a baseline (pretreatment) indicator, useful to identify a patient as a MMF treatment responder or a MMF treatment nonresponder and also as values toward which a non-responder patient must move (perhaps through treatment with other medications) in order to become a MMF treatment responder.
In one embodiment, a control or reference sample includes a composite of data derived from a plurality of nucleic acid microarray hybridizations used to assess gene expression signatures of patients known to respond to MMF treatment, such as microarray hybridizations analyzing MMF treatment responders described herein.
Based on data and principles set forth herein, a subject having or suspected of having scleroderma can be identified as MMF treatment responsive (or likely to respond to MMF treatment) or MMF treatment non-responsive. That a patient or subject is an MMF treatment responder can be confirmed using additional known methods. For example, the patient can be treated with MMF and the effect on mRSS or other indicators of organ involvement assessed. For example, an improvement in mRSS is an indicator of positive response to MMF treatment. In one embodiment, sample classification is performed by Pearson correlations to the average centroid of the genes shown to be up- or down-regulated in each group. Both up- and down-regulated genes can be important. As explained herein, this profile can be measured in skin biopsies of patients with scleroderma using either a gene
18
2613340-2 expression microarray or, especially for small subsets of genes, by a method such as quantitative PCR.
Example 1 Identification of Gene Expression Signatures in SSc Patients Who are MMF Treatment Responders or Non-Responders
A prospective, open-label, observational study was conducted in a clinically well- characterized cohort of SSc patients who were receiving MMF treatment for progressive skin disease in the opinion of the treating physician. Detailed clinical assessments and skin biopsies were performed before the initiation of therapy and at 6 and 12 months during MMF treatment. The purpose of the study was to identify a gene expression signature in skin in MMF treatment responders (responders) and those who do not respond to MMF treatment (non-responders) at baseline (before MMF treatment) and to analyze the differences in the changes in gene expression that occurred in skin during treatment in responders and non- responders. The hypothesis was that the pattern of gene expression in skin at baseline would differ between MMF responders and non-responders, and that there would be alterations in gene expression during MMF treatment in responders, but not in non-responders. The differences between responders and nonresponders can be used to predict or aid in predicting whether an SSc patient will respond to MMF treatment and to assess the effectiveness of MMF treatment.
Patients seen at the Northwestern Scleroderma Program who met American College of Rheumatology criteria for SSc with a mRSS > 16 and would be receiving mycophenolate mofetil for the indication of progressive skin tightening were assessed. All patients provided written informed consent in accordance with the Institutional Review Board Guidelines of Northwestern University. Patients underwent a standardized physical exam, including mRSS performed by one clinician at study entry (prior to treatment) and at 6 months and 12 months post MMF initiation. A pair of skin biopsies was removed from clinically involved skin (forearm) and clinically uninvolved skin (back) from the non- dominant side of the body. Two biopsies (one from forearm and back) were placed in RNAlater® (Applied Biosystems, Ambion®, Carlsbad, California, U.S.A.) and used for DNA microarray analysis and the other biopsy was placed in 10% neutral buffered formalin and used for histological analyses.
Response to MMF was defined as an improvement in mRSS >5, which is the minimal clinically important difference [Amjadi, S., et al., Arthritis Rheum, 2009. 60(8): p. 2490-8] or
19
2613340-2 a >20 improvement in skin score from baseline (which ever was greater) that published studies suggest is a treatment response rather than the natural history of SSc [Khanna, D., et al., Arthritis Rheum, 2007. 56(5): p. 1676-84].
To examine genome-wide changes in gene expression induced by MMF on a cellular level, 200 ng total RNA was amplified and labeled using the Agilent Technologies (Santa Clara, California, U.S.A.) low input fluorescent linear amplification for hybridization as described previously [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696]. Briefly, subject RNA was labeled with Cy3 dye, and Universal Human Reference RNA (UHR) (Stratagene) (Agilent Technologies) was labeled with fluorescent Cy5 dye. After amplification and labeling, the cRNA was purified and co-hybridized with UHR RNA to whole human genome microarrays, representing 41 ,000 unique probes. The hybridization was carried out for 17 hours at 65°C. A total of 89 arrays were hybridized, which included technical replicates.
Arrays were washed and scanned and Gene Pix Pro 5.0 software. Data were Log2 LOWESS normalized for the Cy5/Cy3 ratio, and data was filtered to select array spots with an intensity 2 fold or greater than the local background in either the Cy3 or Cy5 channel. Any probes missing more than 20% of the data across all arrays were omitted from further analysis.
Intrinsic gene analysis was conducted as previously described to identify the genes that are most similar between forearm and back samples for a given individual, but most different between individuals [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696]. For the gene expression of each probe, the algorithm calculated the ratio of the variability within each group of arrays to the variability between each group of arrays. The weighted average of the variance of each group of arrays formed the value of the numerator (A). The weighted average of the gene expression for arrays in each group was calculated and the variance of the average gene expression across all groups of arrays formed the denominator (B). The within group variance divided by the between group variance resulted in an "intrinsic score" for each probe. To determine an FDR value, the gene expression data was permuted multiple times, and the intrinsic gene algorithm was used with each of the permuted gene expression datasets. The average number of probes that were less than a given intrinsic score cutoff in the permuted data was divided by the number of probes that obtained the intrinsic score cutoff in the non-permuted data. This value was multiplied by 100 to provide a percentage FDR rate.
To determine if the baseline gene expression in skin was different between MMF
20
2613340-2 responders and non-responders, and whether MMF responders cluster in the same molecularly defined subset that have been previously described (Diffuse 1 , Diffuse 2, Inflammatory, Normal-like and Limited) [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696], a gene expression analysis was conducted. This analysis identified genes having expression patterns most similar between arm and back biopsies for each subject having the greatest variance among all samples, which has been termed !intrinsic gene analysis' [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696]. The hypothesis was that MMF responders would be members of the inflammatory molecularly defined subset because MMF inhibits lymphocyte proliferation [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696]. Using data obtained from the gene expression study, an unsupervised hierarchical clustering analysis was performed to characterize inherent data-driven groupings (FIG. 1). Included in the experiment were previously analyzed samples from SSc controls (SSc registry), with known molecularly defined signatures. Also included were biopsies from normal healthy controls (Cntrl). The biopsies from the SSc registry and healthy controls were employed to enable identification of the molecularly defined clusters. Findings revealed that expression signatures from pre- treatment (arm and back) biopsies amongst MMF responders (R) and non-responders (NR) were distinctly separate. Further, MMF treatment responders clustered within the inflammatory molecularly defined subset apart from the MMF-non-responders [Milano, A., et al., PLoS One, 2008. 3(7): p. e2696] (FIG. 1).
To identify an MMF responsive gene expression signature in skin at baseline, MMF- responders' baseline gene expression patterns was compared to 6 or 12 month post-MMF treatment levels. Genes having expression that changed concordantly between pre- and post- treatment in arm and back samples were analyzed further. In arm or back samples, 572 genes that had a p<0.002 (FDR 10%) were identified (Table 1). See also Table 1 A. There were dramatic differences in gene expression in arm samples between responders and non- responders at baseline as demonstrated by SAM and cluster analysis (FIG. 2A). The difference in back samples was not as clear, suggesting that skin biopsies from the forearm may be more useful in predicting response to MMF in patients with SSc (FIG. 2B).
To confirm the physical exam finding of softened skin in MMF-responders, the morphology of skin biopsy specimens was examined using routine H&E staining of paraffin embedded sections. There are clear differences in the extent of fibrosis between pre- and post-treatment biopsies in responders. The MMF-nonresponder demonstrated a greater degree in skin fibrosis and a further loss of the normal dermal appendages.
21
2613340-2 TABLE 1
Figure imgf000024_0001
22
2613340-2 Entrez ED Gene Symbol Gene Name Accession
2026 EN02 enolase 2 (gamma, neuronal) NM_001975 solute carrier family 29 (nucleoside
2030 SLC29A 1 transporters), member 1 NM_001078174
2057 EPOR erythropoietin receptor NM_000121 electron-transfer-flavoprotein, alpha
2108 ETFA polypeptide NM_000126
2140 EYA3 Eyes absent homolog 3 (Drosophila) NM_001990 coagulation factor II (thrombin)
2149 F2R receptor NM_001992 coagulation factor VII (serum
2155 F7 prothrombin conversion accelerator) NM_000131
2159 F10 coagulation factor X NM_000504 bromodomain PHD finger transcription
2186 BPTF factor NM_004459
2192 FBLN 1 fibulin 1 NMJXM 996
2199 FBLN2 fibulin 2 NM_001004019
2350 FOLR2 folate receptor 2 (fetal) NM_000803
2662 GDF10 growth differentiation factor 10 NM_004962
2720 GLB 1 galactosidase, beta 1 NM_000404
2743 GLRB glycine receptor, beta NM_000824 guanine nucleotide binding protein (G
2781 GNAZ protein), alpha z polypeptide NM_002073
2821 GPI glucose-6-phosphate isomerase NM_000175
2950 GSTP 1 glutathione S-transferase pi 1 NM_000852 general transcription factor IEF,
2963 GTF2F2 polypeptide 2, 30kDa NM_004128
2969 GTF2I general transcription factor Hi NM_001 163636
2990 GUSB glucuronidase, beta NM_000181
H2A histone family, member Z H2A
histone family, member Z H2A histone
3015 H2AFZ family, member Z NM_002106
High density lipoprotein binding
3069 HDLBP protein NM_005336 histidine triad nucleotide binding
protein 1 histidine triad nucleotide
3094 HINT 1 binding protein 1 NM_005340
3148 HMGB2 High-mobility group box 2 NM_001 130688 inhibitor of DNA binding 3, dominant
3399 ID3 negative helix-loop-helix protein NM_002167 interferon (alpha, beta and omega)
3454 IFNAR 1 receptor 1 NM_000629
3482 IGF2R insulin-like growth factor 2 receptor NM_000876
3667 IRS 1 insulin receptor substrate 1 NM_005544 immunoglobulin superfamily
3671 ISLR containing leucine-rich repeat NM_Q05545
3680 ITGA9 integrin, alpha 9 NM_002207
3693 ITGB5 integrin, beta 5 NM_002213
23
2613340-2 Entrez ED Gene Symbol Gene Name Accession
3913 LAMB2 laminin, beta 2 (laminin S) NM_002292 lysosomal-associated membrane
3916 LAMP 1 protein 1 NM_005561
393 1 LCAT lecithin-cholesterol acyltransferase NM_000229
3984 LIMK 1 LIM domain kinase 1 NM_0023 14 low density lipoprotein receptor-related
4043 LRPAP 1 protein associated protein 1 NM_002337 latent transforming growth factor beta
4054 LTBP3 binding protein 3 NM_001 130144 lymphoblastic leukemia derived
4066 LYL1 sequence 1 NM_005583
MAD2 mitotic arrest deficient-like 1
4085 MAD2L1 (yeast) NM_002358
41 1 1 MAGEA 12 melanoma antigen family A, 12 NM_001 166386 mago-nashi homolog, proliferation-
41 16 MAGOH associated (Drosophila) NM_002370
Mdm4 p53 binding protein homolog
4194 MDM4 (mouse) NM_002393 mannosyl (alpha- 1 ,3-)-glycoprotein
beta- l ,Z-N-
4245 MGAT 1 acetylglucosaminyltransferase NM_001 1 14617 matrix metallopeptidase 15
4324 MMP 15 (membrane-inserted) NM_002428
4515 MTCP 1 mature T-cell proliferation 1 NM_001018025 mitochondrial translational initiation
4528 MTIF2 factor 2 NM_001005369
4628 MYH 10 myosin, heavy chain 10, non-muscle NM_005964
4692 NDN necdin homolog (mouse) NM_002487
NADH dehydrogenase (ubiquinone) 1
4712 NDUFB6 beta subcomplex, 6, 17kDa NM_001 199987
NADH dehydrogenase (ubiquinone)
4729 NDUFV2 flavoprotein 2, 24kDa NM_021074 developmental^ regulated GTP
4733 DRG 1 binding protein 1 NM_004147
4758 NEU 1 sialidase 1 (lysosomal sialidase) NM_000434
4771 NF2 neurofibromin 2 (merlin) NM_000268 nuclear factor (erythroid-derived 2)-
4779 NFE2L 1 like 1 NM_003204
4836 NMT 1 N-myristoyltransferase 1 NM_021079
4853 NOTCH2 notch 2 NM_001200001 nephroblastoma overexpressed gene
4856 NOV nephroblastoma overexpressed gene NM_0025 14 nucleophosmin (nucleolar
4869 NPM 1 phosphoprotein B23, numatrin) N _001037738
4947 OAZ2 ornithine decarboxylase antizyme 2 NM_002537
4952 OCRL oculocerebrorenal syndrome of Lowe NM_000276
4976 OPA 1 optic atrophy 1 (autosomal dominant) NM_015560
24
2613340-2 Entrez ID Gene Symbol Gene Name Accession
serpin peptidase inhibitor, clade A
(alpha- 1 antiproteinase, antitrypsin),
5104 SERPI A5 member 5 NM_000624
51 1 1 PCNA proliferating cell nuclear antigen NM_002592 platelet-derived growth factor receptor,
5159 PDGFRB beta polypeptide NM_002609 pyruvate dehydrogenase kinase,
5163 PDK 1 isozyme 1 NM_002610
5253 PHF2 PHD finger protein 2 NM_005392 procollagen-lysine 1 , 2-oxoglutarate 5-
5351 PLOD1 dioxygenase 1 NM_000302
5393 EXOSC9 exosome component 9 NM_001034194
5420 PODXL podocalyxin-like NM_0010181 1 1 protein phosphatase 1 , regulatory
5514 PPP1R10 (inhibitor) subunit 10 NM_002714
5557 PRIM 1 primase, DNA, polypeptide 1 (49kDa) NM_000946 protein kinase, AMP-activated, beta 2
5565 PRKAB2 non-catalytic subunit NM_005399 mannan-binding lectin serine peptidase
1 (C4/C2 activating component of Ra-
5648 MASP 1 reactive factor) NM_001031849
5664 PSEN2 presenilin 2 (Alzheimer disease 4) NM_000447
5681 PSKH 1 protein serine kinase HI NM_006742 proteasome (prosome, macropain)
5684 PSMA3 subunit, alpha type, 3 NM_002788
5757 PTMA prothymosin, alpha prothymosin, alpha NM_001099285 protein tyrosine phosphatase, non¬
5771 PTPN2 receptor type 2 NM_002828
5828 PEX2 peroxisomal biogenesis factor 2 NM_000318
RAB5A, member RAS oncogene
5868 RAB5A family NM_004162
5884 RAD 17 RAD 17 homolog (S. pombe) NM_002873
5914 RARA retinoic acid receptor, alpha NM_000964
UPF1 regulator of nonsense transcripts
5976 UPF1 homolog (yeast) NM_00291 1
6046 BRD2 bromodomain containing 2 NM_001 1 13182
6050 RNH 1 ribonuclease/angiogenin inhibitor 1 NM_002939
6144 RPL21 ribosomal protein L21 NM_000982
6280 S 100A9 S I 00 calcium binding protein A9 NM_002965
6297 SALL2 sal-like 2 (Drosophila) NM_005407 sodium channel, voltage-gated, type
6330 SCN4B · rv, beta NM_001 142348
6347 CCL2 chemokine (C-C motif) ligand 2 NM_002982
6387 CXCL12 chemokine (C-X-C motif) ligand 12 NM_000609 succinate dehydrogenase complex,
6389 SDHA subunit A, flavoprotein (Fp) NM_004168
6430 SRSF5 serine/arginine-rich splicing factor 5 NM_001039465
25
2613340-2 Entrez ED Gene Symbol Gene Name Accession
splicing factor, suppressor of white-
6433 SFSWAP apricot homolog (Drosophila) NM_004592
ST3 beta-galactoside alpha-2,3-
6483 ST3GAL2 sialyltransferase 2 NM_006927
6586 SLIT3 slit homolog 3 (Drosophila) NM_003062 small nuclear RNA activating complex,
6617 SNAPC 1 polypeptide l , 43kDa NM_003082 small nuclear ribonucleoprotein Dl
6632 SNRPD1 polypeptide 16kDa NM_006938 small nuclear ribonucleoprotein
6636 SNRPF polypeptide F NM_003095
6648 SOD2 superoxide dismutase 2, mitochondrial NM_000636
6659 SOX4 SRY (sex determining region Y)-box 4 NM_003107
6728 SRP19 signal recognition particle 19kDa NM_003135 signal recognition particle receptor
6734 SRPR (docking protein) NM_001 177842
6744 SSFA2 sperm specific antigen 2 NM_001 130445 serine/threonine/tyrosine interacting
6815 STYX protein NM_001 130701
6821 suox sulfite oxidase NM_000456
6836 SURF4 surfeit 4 NM_033161 mitogen-activated protein kinase
6885 MAP3K7 kinase kinase 7 NM_003188
6886 TALI T-cell acute lymphocytic leukemia 1 NM_003189 transcription elongation factor A (SII),
6917 TCEA 1 1 NM_006756 transcription factor 3 (E2A
immunoglobulin enhancer binding
6929 TCF3 factors E 12/E47) NM_001 136139
6942 TCF20 transcription factor 20 (AR 1) NM_005650
7024 TFCP2 transcription factor CP2 NM_001 173452
7031 TFF1 trefoil factor 1 NM_003225 thyroid hormone receptor, alpha
(erythroblastic leukemia viral (v-erb-a)
7067 THRA oncogene homolog, avian) NM_001 190918
7148 TNXB tenascin XB NM_019105
7153 TOP2A topoisomerase (DNA) II alpha 170kDa NM_001067
7187 TRAF3 TNF receptor-associated factor 3 NM_001 199427 triple functional domain (PTPRF
7204 TRIO interacting) NM_0071 18
7272 TTK TTK protein kinase NM_001 166691 ubiquitin-conjugating enzyme E2G 2
7327 UBE2G2 (UBC7 homolog, yeast) NM_001202489
UDP-glucose ceramide
7357 UGCG glucosyltransferase NM_003358
7373 COL14A 1 collagen, type XIV, alpha 1 NM_021 1 10
7596 ZNF45 zinc finger protein 45 NM_003425
26
2613340-2 Entrez ID Gene Symbol Gene Name Accession
7625 ZNF74 zinc finger protein 74 NM 003426
7633 ZNF79 zinc finger protein 79 NM_007135
7743 ZNF189 zinc finger protein 189 NM_003452
7753 ZNF202 zinc finger protein 202 NM_003455
7775 ZNF232 zinc finger protein 232 NM_014519
7798 LUZP 1 leucine zipper protein 1 NM_001 142546 mannosyl-oligosaccharide glucosidase
7841 MOGS mannosyl-oligosaccharide glucosidase NM_001 146158 sema domain, immunoglobulin domain
(Ig), short basic domain, secreted,
(semaphorin) 3B sema domain,
immunoglobulin domain (Ig), short
basic domain, secreted, (semaphorin)
7869 SEMA3B 3B NM_001005914 myeloid/lymphoid or mixed-lineage
8085 MLL2 leukemia 2 NM_003482
8106 PABPN1 Poly(A) binding protein, nuclear 1 NM_004643
8325 FZD8 frizzled homolog 8 (Drosophila) NM_031866
8350 HIST 1 H3A histone cluster 1 , H3a NM_003529
8353 HIST 1 H3E histone cluster 1 , H3e NM_003532
8357 HIST 1 H3H histone cluster 1 , H3h NM_003536
8409 UXT ubiquitously-expressed transcript NM_004182 latent transforming growth factor beta
8425 LTBP4 binding protein 4 NM_001042544
8554 PIAS 1 protein inhibitor of activated STAT, 1 NM_016166
PRP18 pre-mRNA processing factor
8559 PRPF18 18 homolog (S. cerevisiae) NM_003675 aldo-keto reductase family 7, member
8574 AKR7A2 A2 (aflatoxin aldehyde reductase) NM_003689 eukaryotic translation initiation factor
8663 EIF3C 3, subunit C NM_001037808 eukaryotic translation initiation factor
8664 EEF3D 3, subunit D NM_003753
8678 BECN 1 beclin 1 , autophagy related NM_003766
8722 CTSF cathepsin F NM_003793
CDP-diacylglycerol synthase
8760 CDS2 (phosphatidate cytidylyltransferase) 2 NM_003818 receptor-interacting serine-threonine
8767 REPK2 kinase 2 NM_003821
8780 RIOK3 RIO kinase 3 (yeast) NM_003831
8848 TSC22D 1 TSC22 domain family, member 1 NM_006022 prolyl 4-hydroxylase, alpha
8974 P4HA2 polypeptide II NM_001017973
8991 SELENBP1 selenium binding protein 1 NM_003944 apoptosis-inducing factor,
9131 AEFM 1 mitochondrion-associated, 1 NM_001 130846
9139 CBFA2T2 core-binding factor, runt domain, alpha NM_001032999
27
2613340-2 Entrez ED Gene Symbol Gene Name Accession subunit 2; translocated to, 2
9141 PDCD5 programmed cell death 5 NM_004708
DEAD (Asp-Glu-Ala-Asp) box
9188 DDX21 polypeptide 21 NM_004728
9262 STK 17B serine/threonine kinase 17b NM_004226
9320 TRIP 12 thyroid hormone receptor interactor 12 NM_004238
9326 ZNHIT3 zinc finger, HIT-type containing 3 NM_004773
9440 MED 17 mediator complex subunit 17 NM_004268
9476 NAPSA napsin A aspartic peptidase NM_004851
9493 KIF23 kinesin family member 23 NM_004856
9541 CIRl corepressor interacting with RBPJ, 1 NM_004882
ATP synthase, H+ transporting,
9551 ATP5J2 mitochondrial Fo complex, subunit F2 NM_001003713 golgi SNAP receptor complex member
9570 GOSR2 2 NM_00101251 1
9590 A AP12 A kinase (PRKA) anchor protein 12 NM_005100 protein phosphatase 6, regulatory
9701 PPP6R2 subunit 2 NM_014678
9751 SNPH syntaphilin NM_014723
9768 KIAAO IOI KIAAOI OI NM_001029989
9794 MAML1 mastermind-like 1 (Drosophila) NM_014757
9798 KIAA0174 KIAA0174 NM_014761
9805 SCRN1 secernin 1 NM_001 145513
G protein-coupled receptor kinase
9815 GIT2 interacting ArfGAP 2 NM_001 135213
9843 HEPH hephaestin NM_001 130860 tectonin beta-propeller repeat
9895 TECPR2 containing 2 NM_001 172631 aryl -hydrocarbon receptor nuclear
9915 ARNT2 translocator 2 NM_014862 solute carrier family 23 (nucleobase
9962 SLC23A2 transporters), member 2 NM_0051 16
9978 RBX1 ring-box 1 , E3 ubiquitin protein ligase NM_014248
RODl regulator of differentiation 1 (S.
pombe) RODl regulator of
9991 ROD l differentiation 1 (S. pombe) NM_001 163788
10018 BCL2L1 1 BCL2-like 1 1 (apoptosis facilitator) NM_001204106
10040 TOM 1 L1 target of mybl (chicken)-like 1 NM_005486
DnaJ (Hsp40) homolog, subfamily B,
member 6 DnaJ (Hsp40) homolog,
subfamily B, member 6 DnaJ (Hsp40)
10049 DNAJB6 homolog, subfamily B, member 6 NM_005494
CTD (carboxy-terminal domain, RNA
polymerase II, polypeptide A) small
10106 CTDSP2 phosphatase 2 NM_005730
10127 ZNF263 zinc finger protein 263 NM_005741
10135 NAMPT nicotinamide NM_005746
28
2613340-2 Entrez ID Gene Symbol Gene Name Accession phosphoribosyltransferase
nicotinamide
phosphoribosyltransferase
nicotinamide
phosphoribosyltransferase
10161 LPAR6 lysophosphatidic acid receptor 6 NM_001 162497
10168 ZNF197 zinc finger protein 197 NM_001024855
10200 MPHOSPH6 M-phase phosphoprotein 6 NM_005792 eukaryotic translation initiation factor
1 eukaryotic translation initiation
10209 EIF1 factor 1 NM_005801
10231 RCAN2 regulator of calcineurin 2 NM_005822
10391 COR02B coronin, actin binding protein, 2B NM_001 190456
NDC80 homolog, kinetochore complex
10403 NDC80 component (S. cerevisiae) NM_006101
10417 SPON2 spondin 2, extracellular matrix protein NM_001 128325
CD2 (cytoplasmic tail) binding protein
10421 CD2BP2 2 NM_0061 10
C1D nuclear receptor corepressor C 1D
10438 C 1D nuclear receptor corepressor NM_001 190263
10481 HOXB 13 homeobox B 13 NM_006361 vesicle amine transport protein 1
10493 VAT1 homolog (T. californica) NM_006373 acidic (leucine-rich) nuclear
10541 ANP32B phosphoprotein 32 family, member B NM_006401 phosphoribosylaminoimidazole
carboxylase,
phosphoribosylaminoimidazole
10606 PAICS succinocarboxamide synthetase NM_001079524
10609 LEPREL4 leprecan-like 4 NM_006455 hexamethylene bis-acetamide inducible
10614 HEXIM 1 1 NM_006460
10618 TGOLN2 Trans-golgi network protein 2 NM_006464
10670 RRAGA Ras-related GTP binding A NM_006570
10671 DCTN6 dynactin 6 N _006571
10742 RAI2 retinoic acid induced 2 NM_001 172732 mitogen-activated protein kinase
10746 MAP3K2 kinase kinase 2 NM_006609
10766 TOB2 transducer of ERBB2, 2 NM_016272 processing of precursor 4, ribortuclease
10775 POP4 P/MRP subunit (S. cerevisiae) NM_006627
SGTl , suppressor of G2 allele of SKPl
10910 SUGT1 (S. cerevisiae) NM_001 130912
10916 MAGED2 melanoma antigen family D, 2 NM_014599 euchromatic histone-lysine N- methyltransferase 2 euchromatic
10919 EHMT2 histone-lysine N-methyltransferase 2 NM_006709
10923 SUB 1 SUB 1 homolog (S. cerevisiae) NM_006713
29
2613340-2 Entrez ID Gene Symbol Gene Name Accession
processing of precursor 1 , ribonuclease
10940 POP 1 P/MRP subunit (S. cerevisiae) NM 001 145860
1 101 1 TLK2 tousled-like kinase 2 NM_001 1 12707 nudix (nucleoside diphosphate linked
1 1 162 NUDT6 moiety X)-type motif 6 NM_007083 bromodomain adjacent to zinc finger
1 1 177 BAZ1 A domain, 1 A NM_013448
WW domain binding protein 4 (formin
1 1 193 WBP4 binding protein 21 ) NM_007187
1 1328 F BP9 F 506 binding protein 9, 63 kDa NM_007270 pleckstrin homology-like domain,
22822 PHLDA 1 family A, member 1 NM_007350
MORC family CW-type zinc finger 2
22880 MORC2 MORC family CW-type zinc finger 2 NM_014941
22882 ZHX2 zinc fingers and homeoboxes 2 NM_014943
22927 HABP4 hyaluronan binding protein 4 NM_014282
RAB 1 8, member RAS oncogene
22931 RAB 18 family NM_021252 solute carrier family 4 (anion
22950 SLC4A 1 AP exchanger), member 1 , adaptor protein NM_018158 tripartite motif containing 32 tripartite
22954 TRIM32 motif containing 32 NM_001099679 dishevelled associated activator of
morphogenesis 1 dishevelled
associated activator of morphogenesis
23002 DAAM 1 1 NM_014992
23077 MYCBP2 MYC binding protein 2 NM_015057
23160 WDR43 WD repeat domain 43 NM_015131
23176 8-Sep septin 8 NM_00109881 1
ATG4 autophagy related 4 homolog B
23192 ATG4B (S. cerevisiae) NM_013325
TBC 1 (tre-2 USP6, BUB2, cdc l 6)
23216 TBC 1 D 1 domain family, member 1 NMJM 5173
Cdc42 guanine nucleotide exchange
23229 ARHGEF9 factor (GEF) 9 NM_001 173479
23245 ASTN2 astrotactin 2 NM_001 184734
23253 ANKRD 12 ankyrin repeat domain 12 NM_001083625 malonyl-CoA decarboxylase malonyl-
23417 MLYCD CoA decarboxylase NM_012213 solute carrier family 7 (amino acid
23428 SLC7A8 transporter, L-type), member 8 NM_012244 hairy/enhancer-of-split related with
23462 HEY 1 YRPW motif 1 NM_001040708
23466 CBX6 chromobox homolog 6 NM_014292
23468 CBX5 chromobox homolog 5 NM_001 127321 dishevelled associated activator of
23500 DAAM2 morphogenesis 2 NM 001201427
23598 PATZ1 POZ (BTB) and AT hook containing NM_014323
30
2613340-2 Entrez ID Gene Symbol Gene Name Accession zinc finger 1
23636 NUP62 nucleoporin 62kDa NM_001 193357
25758 C l lorf41 chromosome 1 1 open reading frame 41 NM_012194 prostate androgen-regulated mucin-like
25849 PARM 1 protein 1 NM_015393
25888 ZNF473 zinc finger protein 473 NM_001006656
25903 OLFML2B olfactomedin-like 2B NM_015441
25917 THUMPD3 THUMP domain containing 3 NM_001 1 14092
25960 GPR 124 G protein-coupled receptor 124 NM_032777
NECAP endocytosis associated 1
25977 NEC API NECAP endocytosis associated 1 NM_015509
25978 CHMP2B chromatin modifying protein 2B NM_014043 zinc finger and BTB domain
26137 ZBTB20 containing 20 NM_001 164342
26275 HIBCH 3-hydroxyisobutyryl-CoA hydrolase NM_014362
26289 AK5 adenylate kinase 5 NM_012093 hairy/enhancer-of-split related with
26508 HEYL YRPW motif-like NM_014571
26608 TBL2 transducin (beta)-like 2 NM_012453
27042 C lorfl07 chromosome 1 open reading frame 107 NM_014388
ATP synthase, H+ transporting,
mitochondrial Fo complex, subunit s
(factor B) ATP synthase, H+
transporting, mitochondrial Fo
27109 ATP5S complex, subunit s (factor B) NM_001003803 dickkopf homolog 3 (Xenopus laevis)
dickkopf homolog 3 (Xenopus laevis)
27122 DKK3 dickkopf homolog 3 (Xenopus laevis) NM_001018057 methylmalonic aciduria (cobalamin
deficiency) cblD type, with
27249 MMADHC homocystinuria NM_015702
LSM3 homolog, U6 small nuclear
27258 LSM3 RNA associated (S. cerevisiae) NM_014463
Dexi homolog (mouse) Dexi homolog
28955 DEXI (mouse) NM_014015
29015 SLC43A3 solute carrier family 43, member 3 NM_014096
29035 C16orf72 chromosome 16 open reading frame 72 NM_0141 17
29080 CCDC59 coiled-coil domain containing 59 NM_014167
29088 MRPL15 mitochondrial ribosomal protein LI 5 NMJM 4175
DnaJ (Hsp40) homolog, subfamily C,
29103 DNAJC 15 member 15 NM_013238 pyrroline-5-carboxylate reductase
29920 PYCR2 family, member 2 NM_013328 cerebellar degeneration-related protein
30850 CDR2L 2-like NM_014603 potassium channel, subfamily K,
50801 KCNK4 member 4 NM_033310
50861 STMN3 stathmin-like 3 NM_015894
31
2613340-2 Entrez ED Gene Symbol Gene Name Accession
50865 HEBP1 heme binding protein 1 NM_015987
51000 SLC35B3 solute carrier family 35, member B3 NM_001 142540
5 1003 ED31 mediator complex subunit 3 1 NM_Q 16060
5 1063 CALHM2 calcium homeostasis modulator 2 NM_015916 family with sequence similarity 82,
member B family with sequence
51 1 15 FAM82B similarity 82, member B NM_016033
UTP1 1 -like, U3 small nucleolar
51 1 18 UTP1 1 L ribonucleoprotein, (yeast) NM_016037
51 150 SDF4 stromal cell derived factor 4 NM_016176
51 167 CYB5R4 cytochrome b5 reductase 4 NM_016230
51 182 HSPA 14 Heat shock 70kDa protein 14 NM_016299
51 185 CRBN cereblon NM_001 173482
51 199 NIN ninein (GSK3B interacting protein) NM_016350
51246 SHISA5 Shisa homolog 5 (Xenopus laevis) NM_016479
51251 NT5C3 5'-nucleotidase, cytosolic III NM_001002010
51263 MRPL30 mitochondrial ribosomal protein L30 NM_145212
5 1292 GMPR2 guanosine monophosphate reductase 2 NM_001002000
5 1535 PPHLN 1 periphilin 1 NM_001 143787
51540 SCLY selenocysteine lyase NM_016510 phosphatidylinositol glycan anchor
biosynthesis, class T
phosphatidylinositol glycan anchor
51604 PIGT biosynthesis, class T NM_001 184728 ubiquitin-conjugating enzyme E2D 4
51619 UBE2D4 (putative) NM_015983 transmembrane protein 8B
51754 TMEM8B transmembrane protein 8B NM_001042589
53342 IL 17D interleukin 17D NM_138284
53947 A4GALT alpha 1 ,4-galactosyltransferase NM_017436
54149 C21 orf91 chromosome 21 open reading frame 91 NM_001 100420
54206 ERRFI 1 ERBB receptor feedback inhibitor 1 NM_018948 missing oocyte, meiosis regulator,
54468 MIOS homolog (Drosophila) NM_019005
54503 ZDHHC 13 zinc finger, DHHC-type containing 13 NM_001001483
54662 TBC 1 D 13 TBC 1 domain family, member 13 NM_018201 prolyl 4-hydroxylase, transmembrane
(endoplasmic reticulum) prolyl 4- hydroxylase, transmembrane
54681 P4HTM (endoplasmic reticulum) NM_177938 ganglioside induced differentiation
54834 GDAP2 associated protein 2 NM_001 135589
54980 C2orf42 chromosome 2 open reading frame 42 NM_017880 host cell factor C I regulator 1 (XPO l
54985 HCFC 1 R 1 dependent) NM_001002017
Zwilch, kinetochore associated,
55055 ZWILCH homolog (Drosophila) NM_017975
32
2613340-2 Entrez ED Gene Symbol Gene Name Accession
55069 C7orf42 chromosome 7 open reading frame 42 NM_017994
55070 DET1 de-etiolated homolog 1 (Arabidopsis) NM_001 144074
55071 C9orf40 chromosome 9 open reading frame 40 NM_017998
55100 WDR70 WD repeat domain 70 NM_018034
55142 HAUS2 HAUS augmin-like complex, subunit 2 NM_001 130447
55204 GOLPH3L golgi phosphoprotein 3-like NM_018178
Fanconi anemia, complementation
55215 FANCI group I NM_001 1 13378
2-oxoglutarate and iron-dependent
55239 OGFOD 1 oxygenase domain containing 1 NM_018233
55246 CCDC25 coiled-coil domain containing 25 NM_018246 solute carrier family 48 (heme
transporter), member 1 solute carrier
family 48 (heme transporter), member
55652 SLC48A 1 1 NM_017842
55698 RADIL Ras association and DIL domains NM_018059
55742 PARVA parvin, alpha NM_018222
5575 1 TMEM 184C transmembrane protein 184C NM_018241 lysine (K)-specific demethylase 3A
lysine (K)-specific demethylase 3A
55818 KDM3A lysine (K)-specific demethylase 3A NM_001 146688
55839 CENPN centromere protein N NM_001 100624 integrin alpha FG-GAP repeat
55846 ITFG2 containing 2 NM_018463
55872 PBK PDZ binding kinase NM_018492
55892 MYNN myoneurin NM_001 1851 18 asparagine-linked glycosylation 1 ,
beta- 1 ,4-mannosyltransferase homolog
56052 ALG 1 (S. cerevisiae) NM_019109
56257 MEPCE methylphosphate capping enzyme NM_001 194990
56658 TRIM39 tripartite motif containing 39 NM_021253
56683 C21 orf59 chromosome 21 open reading frame 59 NM_021254
5673 1 SLC2A4RG SLC2A4 regulator NM_020062
56925 LXN latexin NM_020169 aryl hydrocarbon receptor nuclear
56938 ARNTL2 translocator-like 2 NM_020183
56963 RGMA RGM domain family, member A N _001 166283
56974 DKFZp547K054 hypothetical protein DKFZp547K054 AL390175. 1
56981 PRDM 1 1 PR domain containing 1 1 NM_020229
56992 KIF15 kinesin family member 15 NM_020242
57082 CASC5 cancer susceptibility candidate 5 NM_ 144508
57128 LYRM4 LYR motif containing 4 NM_001 164840 mannosidase, alpha, class 1 C, member
57134 MAN 1 C 1 1 NM_020379
57178 ZM1Z 1 zinc finger, MIZ-type containing 1 NM_020338
57212 KIAA0495 KIAA0495 NR_033708.1
57226 LYRM2 LYR motif containing 2 LYR motif NM_020466
33
2613340-2 Entrez ED Gene Symbol Gene Name Accession
containing 2
SPC25, NDC80 kinetochore complex
57405 SPC25 component, homolog (S. cerevisiae) N _020675
57446 NDRG3 NDRG family member 3 NM_022477
57456 KIAA 1 143 IAA 1 143 NM_020696 vacuolar protein sorting 18 homolog
57617 VPS 18 (S. cerevisiae) N _020857 pleckstrin homology domain
containing, family A (phosphoinositide
57664 PLEKHA4 binding specific) member 4 NM_001 161354
57692 MAGEE1 melanoma antigen family E, 1 NM_020932
57701 NC AP5L NCK-associated protein 5-like NM_001037806
CTD (carboxy-terminal domain, R A
polymerase II, polypeptide A) small
58190 CTDSP1 phosphatase 1 NM_021 198 tumor protein p53 inducible nuclear
58476 TP53ENP2 protein 2 NM_021202
58491 ZNF71 zinc finger protein 71 NM_021216 guanine nucleotide binding protein (G
59345 GNB4 protein), beta polypeptide 4 NM_021629 solute carrier family 25 (mitochondrial
thiamine pyrophosphate carrier),
60386 SLC25A19 member 19 NM_001 126121
60492 CCDC90B coiled-coil domain containing 90B NM_021825 resistance to inhibitors of
cholinesterase 8 homolog A (C.
60626 RIC8A elegans) NM_021932
VPS33B interacting protein, apical-
63894 VEPAR basolateral polarity regulator NM_001 193314
64219 PJA 1 Praja ring finger 1 NM_001032396
64326 RFWD2 ring finger and WD repeat domain 2 NM_001001740
64766 S 100PBP S I OOP binding protein NM_001017406
65265 C8orf33 chromosome 8 open reading frame 33 NM_023080
79041 TMEM38A transmembrane protein 38A NM_024074
79072 FASTKD3 FAST kinase domains 3 NM_024091
79083 MLPH melanophilin melanophilin NM_001042467
79084 WDR77 WD repeat domain 77 NM_024102
79178 THTPA thiamine triphosphatase NM_001 126339
79447 C 16orf53 chromosome 16 open reading frame 53 NM_024516
79600 TCTN 1 tectonic family member 1 NM_001082537
79634 SCRN3 secernin 3 NM_001 193528 phosphopantothenoylcysteine
79717 PPCS synthetase NM_001077447 suppressor of variegation 3-9 homolog
79723 SUV39H2 2 (Drosophila) NM_001 193424
79768 C 15orf29 chromosome 15 open reading frame 29 NM_024713
79812 MMRN2 multimerin 2 NM_024756
34
2613340-2 Entrez ID Gene Symbol Gene Name Accession
79825 CCDC48 coiled-coil domain containing 48 NM_024768 zinc finger and BTB domain
79842 ZBTB3 containing 3 NM_024784 dephospho-CoA kinase domain
79877 DCAKD containing NM_001 128631
79992 NCRNA00241 non-protein coding RNA 241 A 026765.1
80079 F 13769 hypothetical protein FU 13769 XR_040824.1
EF-hand domain (C-terminal)
80258 EFHC2 containing 2 NM_025 184
80303 EFHD 1 EF-hand domain family, member D l NM_025202
80745 THUMPD2 THUMP domain containing 2 NM_025264
80760 ITIH5 Inter-alpha (globulin) inhibitor H5 NM_001001851
80818 ZNF436 zinc finger protein 436 NM_001077195
80824 DUSP 16 Dual specificity phosphatase 16 NM_030640
81562 LMAN2L lectin, mannose-binding 2-like NM_001 142292 non imprinted in Prader-
81614 NIPA2 Willi/Angelman syndrome 2 NM_001008860
81618 ITM2C integral membrane protein 2C NM_001012514 iron-sulfur cluster assembly 1 homolog
81689 ISCA 1 (S. cerevisiae) NM_030940 chromosome 14 open reading frame
81892 C 14orfl 56 156 NM_031210
81930 KIF 18A kinesin family member 18A NM_031217 cysteine-rich secretory protein LCCL
83716 CRISPLD2 domain containing 2 NM_031476
83742 MARVELD 1 MARVEL domain containing 1 NM_031484
83759 RBM4B RNA binding motif protein 4B NM_031492
ATPase family, AAA domain
83858 ATAD3B containing 3B NM_031921
83931 STK40 serine/threonine kinase 40 NM_032017
83932 C l orfl 24 chromosome 1 open reading frame 124 NM_001010984 ankyrin repeat domain 27 (VPS9
84079 AN RD27 domain) NM_032139
UTP 15, U3 small nucleolar
ribonucleoprotein, homolog (S.
84135 UTP 15 cerevisiae) NM_032175 solute carrier family 7, member 6
84138 SLC7A60S opposite strand NM_032178 ribosome production factor 2 homolog
84154 RPF2 (S. cerevisiae) NM_032194
84168 ANTXR 1 anthrax toxin receptor 1 NM_018153 polymerase (RNA) I polypeptide B,
84172 POLR 1 B 128kDa NM_001 137604
84236 RHBDD 1 rhomboid domain containing 1 NM_001 167608
84246 MED I O mediator complex subunit 10 NM_032286 leucine zipper, down-regulated in
84247 LDOC 1 L cancer 1 -like NM_032287
35
2613340-2 Entrez ID Gene Symbol Gene Name Accession
84268 RPAIN RPA interacting protein NM_001033002
LLP homolog, long-term synaptic
84298 LLPH facilitation (Aplysia) NM_032338
SLX4 structure-specific endonuclease
84464 SLX4 subunit homolog (S. cerevisiae) NM_032444
84498 FAM 120B family with sequence similarity 120B NM_032448 minichromosome maintenance
84515 MCM8 complex component 8 NM_032485
84661 DPY30 dpy-30 homolog (C. elegans) NM_032574 cytochrome c oxidase subunit IV
84701 COX4I2 isoform 2 (lung) NM_032609 fucosyltransferase 10 (alpha ( 1 ,3)
84750 FUT10 fucosyltransferase) NM_032664
UDP-GlcNAc:betaGal beta- l ,3-N-
84752 B3GNT9 acetylglucosaminyltransferase 9 NM_033309
84775 ZNF607 zinc finger protein 607 NM_001 172677 phosphatidic acid phosphatase type 2
84814 PPAPDC3 domain containing 3 NM_032728
84826 SFT2D3 SFT2 domain containing 3 NM_032740
84865 CCDC 142 coiled-coil domain containing 142 NM_032779
84866 TMEM25 transmembrane protein 25 NM_001 144034
84872 ZC3H 10 zinc finger CCCH-type containing 10 NM_032786
84886 C l orfl 98 chromosome 1 open reading frame 198 NM_001 136494 leucine rich repeat and Ig domain
84894 LINGO 1 containing 1 NM_032808 microtubule associated
84930 MASTL serine/threonine kinase-like NM_001 172303 melanoma associated antigen (mutated)
84939 MUM 1 1 NM_032853
84952 CGNL1 cingulin-like 1 NM_032866
RAS-like, estrogen-regulated, growth
85004 RERG inhibitor NM_001 190726 progestin and adipoQ receptor family
853 15 PAQR8 member VIII NM_133367
85376 RIMBP3 RIMS binding protein 3 NM_015672
90293 KLHL13 kelch-like 13 (Drosophila) NM_001 168299
90324 CCDC97 coiled-coil domain containing 97 NM_052848
90780 PYG02 pygopus homolog 2 (Drosophila) NM_ 138300
UDP-N-acteylglucosamine
91373 UAP 1 L 1 pyrophosphorylase 1 -like 1 NM_207309
91408 BTF3L4 basic transcription factor 3-like 4 NM_001 136497
92140 MTDH metadherin NM_178812
92181 UBTD2 ubiquitin domain containing 2 NM_152277
92595 ZNF764 zinc finger protein 764 NM_001 172679
CENPB DNA-binding domains
92806 CENPBD 1 containing 1 NM J45039
92856 IMP4 IMP4, U3 small nucleolar NM_033416
36
2613340-2 Entrez ID Gene Symbol Gene Name Accession ribonucleoprotein, homolog (yeast)
zinc finger and BTB domain
containing 47 zinc finger and BTB
92999 ZBTB47 domain containing 47 NM_145166
94039 ZNF101 zinc finger protein 101 NM_033204
94121 SYTL4 synaptotagmin-like 4 NM_001 129896 family with sequence similarity 54,
1 131 15 FAM54A member A NM_001099286 carbohydrate (N-acetylgalactosamine
1 13189 CHST 14 4-0) sulfotransferase 14 NM_ 130468 cytochrome P450, family 2, subfamily
1 13612 CYP2U 1 U, polypeptide 1 NM_183075
1 14824 PNMA5 paraneoplastic antigen like 5 NM_001 103150 odd-skipped related 2 (Drosophila)
1 16039 OSR2 odd-skipped related 2 (Drosophila) NM_001 142462
1 17581 TWIST2 twist homolog 2 (Drosophila) NM_057179 coiled-coil-helix-coiled-coil-helix
1 18487 CHCHD 1 domain containing 1 NM_203298
12201 1 CSNK1 A 1 L casein kinase 1 , alpha 1 -like NM_ 145203
123096 SLC25A29 solute carrier family 25, member 29 NM_001039355
123207 C 15orf40 chromosome 15 open reading frame 40 NM_001 1601 13 hexamthylene bis-acetamide inducible
124790 HEXEM2 2 NM_ 144608
125058 TBC 1 D 16 TBC 1 domain family, member 16 NM_019020
126006 PCP2 Purkinje cell protein 2 NM_ 174895
127703 C l orf216 chromosome 1 open reading frame 216 NM_152374
128637 TBC 1 D20 TBC 1 domain family, member 20 NM_ 144628
129804 FBLN7 fibulin 7 NM_001 128165
129807 NEU4 sialidase 4 sialidase 4 NM_001 167599
131965 METTL6 methyltransferase like 6 NM_152396
EGF-like, fibronectin type III and
133584 EGFLAM laminin G domains NM_ 152403 chromosome 20 open reading frame
140706 C20orfl 60 160 NM_080625
14083 1 ZSWIM3 zinc finger, SWEM-type containing 3 NM_080752
140862 ISM 1 isthmin 1 homolog (zebrafish) NM_080826
A 057359.1 ,
146346 LOC I 46346 hypothetical protein LOC I 46346 BX648396.1
148223 C I 9orf25 chromosome 19 open reading frame 25 NM_152482
MOB 1 , Mps One Binder kinase
148932 MOBKL2C activator-like 2C (yeast) NM_ 145279
1491 1 1 CNIH3 cornichon homolog 3 (Drosophila) NM_ 152495 membrane bound O-acyltransferase
154141 MBOAT 1 domain containing 1 NM_001080480
154796 AMOT angiomotin NM_001 1 13490
155061 ZNF746 zinc finger protein 746 NM_001 163474
157247 MGC27345 hypothetical protein MGC27345 XR_108807.1
37
2613340-2 Entrez ED Gene Symbol Gene Name Accession
family with sequence similarity 120A
158293 FAM 120AOS opposite strand NM_ 198841
163049 ZNF791 zinc finger protein 791 NM_153358
DEAH (Asp-Glu-Ala-His) box
170506 DHX36 polypeptide 36 NM_001 1 14397
199745 THAP8 THAP domain containing 8 NM_ 152658 asparagine-linked glycosylation 14
199857 ALG 14 homolog (S. cerevisiae) NM_ 144988
200728 TMEM 17 transmembrane protein 17 NM_198276
201 163 FLCN folliculin NM_ 144606
219539 YPEL4 yippee-like 4 (Drosophila) NM_ 145008 heterogeneous nuclear
220988 HNRNPA3 ribonucleoprotein A3 NM_ 194247
221362 LOC221362 hypothetical protein LOC221362 XP_001 134277.1
221442 LOC221442 adenylate cyclase 10 pseudogene NR_026938.2
223082 ZNRF2 zinc and ring finger 2 NM_147128
245812 CNPY4 canopy 4 homolog (zebrafish) NM_152755
255326 LOC255326 hypothetical protein LOC255326 NR_00361 1.2
255458 LOC255458 hypothetical protein LOC255458 NR_027183.1
256691 MAMDC2 MAM domain containing 2 NM_153267 asp (abnormal spindle) homolog,
259266 ASPM microcephaly associated (Drosophila) NM_018136
283130 SLC25A45 solute carrier family 25, member 45 NM_001077241 family with sequence similarity 177,
283635 FAM 177A 1 member A 1 NM_001079519
284542 LOC284542 hypothetical protein LOC284542 NM_001 194986.1 immunoglobulin superfamily, member
285313 IGSF10 10 NM_001 178145
285958 C7orf40 chromosome 7 open reading frame 40 NR 003697.1 zinc finger and BTB domain
339487 ZBTB80S containing 8 opposite strand NM_178547
342892 ZNF850 zinc finger protein 850 NM_001 193552
360132 F BP9L FK506 binding protein 9-like NR_003949.1
375096 FLJ44670 FLJ44670 protein NM_080627.2 solute carrier family 27 (fatty acid
376497 SLC27A 1 transporter), member 1 NM_198580
389033 LOC389033 placenta-specific 9 pseudogene NR_026740.1 similar to peptidylprolyl isomerase A
390299 LOC390299 isoform 1 XM_372452.4
400604 LOC400604 hypothetical LOC400604 XR_ 109405.1
400629 TEX 19 testis expressed 19 NM_207459 heat shock factor binding protein 1 -like
440498 HSBP1 L1 1 NM_001 136180 similar to Gamma- glutamyltranspeptidase 1 precursor
(Gamma-glutamyltransferase 1 )
440796 LOC440796 (CD224 antigen) NR_003267.1
38
2613340-2 Example 2 Classification of SSc into Subtypes
As described previously (USSN 13/054,244), Applicant has shown that five distinct SSc subtypes can be identified by different gene expression profiles of a set of intrinsic genes. As used herein, an "intrinsic gene" is a gene that shows little variance within repeated samplings of tissue from an individual subject having scleroderma, but which shows high variance across the same tissue in multiple subjects, wherein the multiple subjects include both subjects having scleroderma and subjects not having scleroderma. For example, an intrinsic gene can be a gene that shows little variance within repeated samplings of forearm- back skin pairs in a subject having scleroderma, but which shows high variance across forearm-back skin pairs of other subjects, wherein the other subjects include both subjects having scleroderma and subjects not having scleroderma.
An intrinsic gene set is a group of genes including one or more intrinsic genes. A minimal intrinsic gene set is defined herein as being derived from an intrinsic gene set, and is comprised of the smallest number of intrinsic genes that can be used to classify a sample.
As described previously, intrinsic gene sets were used to classify scleroderma into a Diffuse-Proliferation group or subtype thereof, Inflammatory group, Limited group or Normal-Like group. The Diffuse-Proliferation group is composed solely of patients with a diagnosis of dSSc. The Inflammatory group includes patients with dSSc, ISSc and morphea. The Limited group is composed solely of patients with ISSc. The Normal-Like group includes healthy controls along with dSSc and ISSc patients. These intrinsic groups or subsets create a more refined division of the disease than current clinical diagnoses and allow for the assessment of patients in different subsets and their likelihood of responding to therapy. For example, it has been shown that patients in the Diffuse-Proliferation group are likely to respond to the drug imatinib mesylate, marketed under the trade name of GLEEVEC® (Novartis Pharmaceuticals, East Hanover, NJ). Furthermore, selected genes from this gene expression signature provide a basis for identifying patients having, or at risk of having, ILD or digital ulcer involvement.
Based on analysis of the ca. 1000 identified intrinsic genes as disclosed, it was possible to categorize non-overlapping sets of genes from within these approximately 1000 intrinsic genes that differentiate the Diffuse-Proliferation group, the inflammatory group, the Limited group, and the Normal-Like group.
Genes that differentiate the Diffuse-Proliferation group. There are two major sets of genes that differentiate the Diffuse-Proliferation group. One set (Group I) shows higher
39
2613340-2 expression in the Diffuse-Proliferation group and the other set (Group II) shows lower expression in the Diffuse-Proliferation group. The Diffuse-Proliferation group is also defined in part by the general absence of an Inflammatory signature, although there can be some overlap between the Inflammatory and Diffuse-Proliferation signatures.
Group I genes include 138 genes, the increased expression of which is indicative of the Diffuse-Proliferation group. Expression of these genes is decreased in the Inflammatory, Limited, and Normal-Like groups. Referring to Table 3 below, included in the genes of Group I are the following genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C12orfl4, C14orfl31, CACNG6, CBLLl, CBX8, CDC7, CDTl, CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1, FGF5, FLJ 10902, FLJ 12438, FLJ 12443, FLJ 12484, FLJ 12572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS3, IKBKG, IL23A, DNSIG1, KIAA1509, KIAA1609, KIAA1666, LDLR, LGALS8, LILRB5, LOC123876, LOC128977, LOC153561, LOC283464, LRRIQ2, LY6K, MAC30, ME2, MGC13186, MGC 16044, MGC 16075, MGC29784, MGC33839, MGC35212, MGC4293, MICB, MLL5, MTRF1L, MUC20, NICNl, NPTX1, OAS3, OGDHL, OPRK1, PCNT2, PDZK1, P1TPNC1, PPFIA4, PREB, PR Y, PSMD11, PSPH, PSPHL, PTP4A3, PXMP2, RAB15, RAD51 API, RIP, RNF121, RPL41, RPS18, RPS4Y1, RPS4Y2, SI OOP, SORD, SP1, SY P , SYT6, T 9SF4, TMOD3, TNFRSF12A, TPRA40, TRIP, TRPM7, TTR, TUBB4, VARS2L, ZNF572, and ZSCAN2. Also included in the genes of Group I are the following genes, each identified by GenBank accession number only: A_24_BS934268, AB065507, AC007051, AI791206, A 022745, AK022893, A 022997, AK094044, AL391244, AL731541, AL928970, BC010544, BC020847, BM925639, BM928667, ENST00000328708, ENST00000333517, L1891291, 1_3580313, NM_001009569, NM_001024808, NM_172020, NM_173705, NM_178467, NR_001544, THC1434038, THC1484458, THC1504780, U62539,
XM_210579, XM_303638, and XM_371684.
Group II genes include 298 genes, the decreased expression of which is also indicative of the Diffuse- Proliferation group. Expression of these genes is increased in the Inflammatory, Limited, and Normal-Like groups. Referring to Table 3 below, included in the genes of Group II are the following genes, each identified by name: AADAC, ADAM17, ADH1A, ADH1C, AHNA , ALG1, ALG5, AMOT, AOX1, AP2A2, AR 5, ARL6EP5, ARMCX1, BECN1, BECN1, BMP8A, BNIP3L, ClOorfl 19, Clorf24, C lorf37, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6,
40
2613340-2 CCNG2, CDC26, CDK2AP1, CDRl, CFHLl, CNTN3, CPNE5, CRTAP, CTNNAl, CTSC, CUTL1, CXCL5, CYBRD1, CYP2R1, DBN1, DCAMKL1, DCL-1 , DIAPH2, DK 2, ECHDC3, ECM2, EEF3S7, EMB, EMCN, EMILIN2, ENPP2, EPB41L2, FBLN1, FBLN2, FEM1A, FGL2, FHL5, F BP7, FLU, FU10986, FLJ20032, FLJ20701, FLJ23861,
FLJ34969, FU36748, FLJ36888, FLJ43339, FZR1, GABPB2, GARNL4, GHITM, GHR, GIT2, GLYAT, GPM6B, GTPBP5, HELB, HOXB4, IFNA6, IGFBP5, IL13RA1, IL15, KAZALDl, KCNK4, KCNS3, KCTDIO, KIAA0232, KIAA0494, KIAA0562, KIAA0870, KIAA1190, KIF25, KLHL18, KLK2, LAMP2, LEPR0TL1, LHFP, LM02, LOCI 14990, LOC255458, LOC387680, LOC400027, LOC493869, LOC87769, LRBA, AFB,
MAGEH1, MAN2B2, MCCC2, MEGF10, MFAP5, MGC11308, MGC15523, MGC3200, MGC35048, MGC45780, MOGAT3, MPPE1, MPZ, MY01B, MYOC, NFYC,
NIPSNAP3B, OPTN, OSR2, PAM, PBXIP1, PCOLCE2, PDGFC, PDGFRA, PDGFRL, PEX19, PHAX, PIP, PKM2, PKP2, PMP22, POU2F1, PPAP2B, PRAC, PSMA5,
PSORS1C1, PTGIS, RECK, RGS11, RGS5, RIMS3, RIPK2, RNASE4, RNF125, RNF13, RNF146, RNF19, ROBOl, ROB03, RPL7A, SARAl, SAVl, SCGBIDI, SDKl, SECP43, SECTM1, SERPINB2, SGCA, SH3BGRL, SH3GLB1, SH3RF2, SLC10A3, SLC12A2, SLC14A1, SLC39A14, SLC7A7, SLC9A9, SLPI, SMAD1, SMAP1, SMARCE1, SMP1, SNTG2, SNX7, SOCS5, SSPN, STX7, SUMF1 , TAS2R10, TDE2, TFAP2B, TGFBR2, THSD2, TM4SF3, TMEM25, TMEM34, TNA, TNKS2, TRAD, TRAF3IP1, TREM4, TRIM35, TRIM9, TTYH2, TUBBl, UBL3, ULK2, URB, USP54, UST, UTRN, UTX, WIFl, WWOX, XG, YPEL5, and ZFHX1B. Also included in the genes of Group II are the following genes, each identified by GenBank accession number only: A_32_BS 169243, A_32_BS200773, A_32_BS53976, AC025463, AF124368, AF161364, AF318337,
AF372624, AK001565, AK022793, AK055621, AK056856, AL050042, AL137761, BC035102, BC038761, BC039664, BG252130, BIO 14689, D80006, ENST00000298643, ENST00000300068, ENST00000305402, ENST00000307901, ENST00000321656, ENST00000322803, ENST00000329246, ENST00000331640, ENST00000332271, ENST00000333784, H16080, 1_1861543, 1_1882608, I_l 985061, 1_3335767, L3551568, L3588329, 1_932413, 1_962800, 1_966091, NM_001008528, NM_001009555,
NM_001013632, NM_001014975, NM_001018006, NM_001018076, NM_001025077, NM_003671, NM_014758, NM_015262, NM_138411, NM_153030, NM_173709,
NM_213595, NR_002184, S62210, THC 1419743, THC 1429821, THC 1457118,
THC 1459712, THC 1461073, THC 1506312, THC 1511927, THC 1515028, THC 1525318,
41
2613340-2 THC1531579, THC1544941, THC1551463, THC1559236, THC1560798, THC1563147, THC1572906, THC1574967, THC1591470, XM_165930, and XM_209429.
Genes that differentiate the Inflammatory group. The Inflammatory group is identified by increased expression of a group of 119 genes in Group III. These genes show low expression in the Diffuse-Proliferation, Limited, and Normal-Like groups. Referring to Table 3 below, included in the genes of Group III are the following genes, each identified by name: A2M, ADF1, ALOX5AP, APOL2, APOL3, BATF, BCL3, BIRCl, BTN3A2, ClOorflO, Clorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTLl, CPA3, CPVL, CTAGIB, DDX58, EBI2, EVI2B, F13A1, FAM20A, FAP, FCGR3A, FUl 1259, FLI22573, FLJ23221, FLJ25200, FYB, GBP1, GBP3, GEM, GIMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLS1, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB 1, HLA-DQA1, HLA- DQA2, HLA-DQB 1 , HLA-DRB 1 , HLA-DRB5, ICAM2, EFI16, IFI16, IFIT1, EFIT2, MTMl, ΓΕΙΤΜ2, IFITM3, ILIORA, INDO, ITGB2, KIAA0063, LAMBl, LCPl, LGALS2, LGALS9, LILRB2, LOC387763, LOC400759, LUM, LYZ, MARCKS, MFNG, MGC24133, MPEG1, MRC1, MRCL3, MS4A6A, MX1, NNMT, NUP62, PAG, PLAU, PPIC, PPIC, PTPRC, RAC2, RGS10, RGS16, RSAFD1, SAT, SCGB2A1, SLC20A1, SLC02B1, SPARC, SULF1, TAP1, TCTEL1, TIMP1, TNFSF4, UBD, VSIG4, and ZFYVE26. Also included in the genes of Group III are the following genes, each identified by GenBank accession number only: AF533936, BQ049338, ENST00000310210, ENST00000313904, ENST00000329660, 1_1000437, 1_966691, M15073, NM_001010919, NM_001025201, NM_001033569, THC 1543691, and XM_291496.
In one embodiment the Inflammatory group, and likewise a subject that can be categorized as falling within the Inflammatory group, can be identified by the increased expression of any one or more genes within Group III.
In one embodiment the Inflammatory group, and likewise a subject that can be categorized as falling within the Inflammatory group, can be identified by the increased expression of any one or more genes within Group III and the decreased expression of any one or more genes in Group I.
In one embodiment the Inflammatory group, and likewise a subject that can be categorized as falling within the Inflammatory group, can be identified by the increased expression of any one or more genes within Group III and the increased expression of any one or more genes within Group II.
42
2613340-2 In one embodiment the Inflammatory group, and likewise a subject that can be categorized as falling within the Inflammatory group, can be identified by the increased expression of any one or more genes within Group III, the decreased expression of any one or more genes in Group I, and the increased expression of any one or more genes within Group II.
TABLE 3
Figure imgf000045_0001
43
2613340-2 ATPase, H+ transporting, lysosomal 56/58kDa,
ATP6V 1B2 NM_001693
V I subunit B, isoform 2
AVPI 1 Arginine vasopressin-induced 1 NM_021732
AXL AXL receptor tyrosine kinase NM_001699
UDP-Gal:betaGal beta 1 ,3-galactosyltransferase
B3GALT6 NM_080605 polypeptide 6
Beta-l ,3-glucuronyltransferase 3
B3GAT3 NM_012200
(glucuronosyltransferase 1)
B3GTL Beta 3-glycosyltransferase-like BC032021
BAALC Brain and acute leukemia, cytoplasmic NM 024812
Basic leucine zipper transcription factor, ATF-
BATF N _006399 like
BCAR 1 Breast cancer anti-estrogen resistance 1 NM_014567
Branched chain keto acid dehydrogenase E l , beta
BCKDHB NM_ 183050 polypeptide (maple syrup urine disease)
BCL3 B-cell CLL/lymphoma 3 NM_005178
Beclin 1 (coiled-coil, myosin-like BCL2
BECN 1 NM_003766 interacting protein)
Beclin 1 (coiled-coil, myosin-like BCL2
BECN 1 NM_003766 interacting protein)
BEXL 1 Brain expressed X-linked-like 1 XM_043653
BIRC l Baculoviral IAP repeat-containing 1 NM_004536
Bles03 Basophilic leukemia expressed protein BLES03 NM 031450
BMP8A Bone morphogenetic protein 8a AK093659
BCL2/adeno virus EIB 19kDa interacting protein
BNIP3L AF067396
3-like
BCL2/adenovirus E I B 19kDa interacting protein
BNIP3L NM_004331
3-like
BTN3A2 Butyrophilin, subfamily 3, member A2 NM_007047
C lOorfl O Chromosome 10 open reading frame 10 NM_007021
C10orfl l9 Chromosome 10 open reading frame 1 19 NM_024834
C10orf9 Chromosome 10 open reading frame 9 NM_145012
C 12orfl4 Chromosome 12 open reading frame 14 NM_021238
C14orfl 31 Chromosome 14 open reading frame 131 NM_018335 .
Clorf24 Chromosome 1 open reading frame 24 NM 052966
C lor07 Chromosome 1 open reading frame 37 CR591805
C I 01-O8 Chromosome 1 open reading frame 38 NMJ304848
Clorf42 Chromosome 1 open reading frame 42 NM_019060
C20orfl0 Chromosome 20 open reading frame 10 NM_014477
C20orf22 Chromosome 20 open reading frame 22 NM 015600
GPI-anchored metastasis-associated protein
C4.4A NM_014400 homolog
C5orfl4 Chromosome 5 open reading frame 14 NM_024715
C6orf27 Chromosome 6 open reading frame 27 NM_025258
C6orf64 Chromosome 6 open reading frame 64 NM_018322
C6orf80 Chromosome 6 open reading frame 80 NM 015439
C7orfl9 Chromosome 7 open reading frame 19 NM 032831
C9orf61 Chromosome 9 open reading frame 61 NM_004816
CABP7 Calcium binding protein 7 NM_ 182527
Calcium channel, voltage-dependent, alpha
CACNA2D 1 NM_000722
2/delta subunit 1
Calcium channel, voltage-dependent, gamma
CACNG6 NM_145814 subunit 6
CAPN IO Calpain 10 NM_021251
CAPS Calcyphosine NM_004058
CASP4 Caspase 4, apoptosis-related cysteine protease NM_033307
CASP5 Caspase 5, apoptosis-related cysteine protease NM 004347
CAST Calpastatin NM_ 173060
44
-2 CAV2 Caveolin 2 ■ NMJXM233
Cas-Br-M (murine) ecotropic retroviral
CBLL1 NM_0248 I4 transforming sequence-like 1
Chromobox homolog 8 (Pc class homolog,
CBX8 NM_020649
Drosophila)
CCDC6 Coiled-coil domain containing 6 S72869
CCL2 Chemokine (C-C motif) ligand 2 NM_002982
CCL4 Chemokine (C-C motif) ligand 4 NM_002984
CCNG2 Cyclin G2 NM_004354
CCNG2 Cyclin G2 NM_004354
CCNT2 Cyclin T2 NM_058241
CCR5 Chemokine (C-C motif) receptor 5 NM_000579
CCT5 Chaperonin containing TCP1 , subunit 5 (epsilon) NM_012073
CD33 CD33 antigen (gp67) NM_001772
CD86 antigen (CD28 antigen ligand 2, B7-2
CD86 NM_006889 antigen)
CD8A CD8 antigen, alpha polypeptide (p32) NM_001768
CDC26 Cell division cycle 26 NM_139286
CDC37 cell division cycle 37 homolog (S.
CDC37 NM_00706S cerevisiae)
CDC7 CDC7 cell division cycle 7 (S. cerevisiae) NM_003503
CD 2AP1 CDK2-associated protein 1 NM_004642
CDR 1 Cerebellar degeneration-related protein 1 , 34kDa NM 004065
CDT1 DNA replication factor NM_030928
CDW52 CDW52 antigen (CAMPATH- I antigen) NM_001803
CEBPD CCAAT/enhancer binding protein (C/EBP), delta NM_005195
CENPE Centromere protein E, 312kDa NM_OOI 813
CFHL1 Complement factor H-related 1 NM_0021 13
CGI- 1 1 1 CGI-1 1 1 protein NM_016048
CGI-90 CGI-90 protein NM_016033
CISH Cytokine inducible SH2 -containing protein NM_ 145071
C LFSF1 Chemokine-like factor super family 1 NMJ 81294
CLDN6 Claudin 6 NM_02 I 195
CLIPR-59 CLIP- 170-related protein BCOI 31 16
CLYBL Citrate lyase beta like ' NM_ 138280
CNFN Cornifelin NM_032488
CNTN3 Contactin 3 (plasmacytoma associated) AB040929
C0L1 A2 Collagen, type I, alpha 2 NM 000089
COL6A2 Collagen, type VI, alpha 2 NM_001849
COL6A3 Collagen, type VI, alpha 3 NM_057165
C0MMD2 COMM domain containing 2 NM_016094
C0TL 1 Coactosin-like 1 (Dictyostelium) NM_021 149
COX5A Cytochrome c oxidase subunit Va AA 129107
CPA3 Carboxypeptidase A3 (mast cell) NM_001870
CPNE5 Copine V NM 020939
CPVL Carboxypeptidase, vitellogenic-like NM_019029
CRBN Cereblon AF1301 17
CAMP responsive element binding protein 3-like
CREB3L3 NM_032607
3
CRLF1 Cytokine receptor-like factor 1 NM 004750
CROC4 Transcriptional activator of the c-fos promoter NM 006365
CRTAP Cartilage associated protein NM_006371
CTAG 1 B Cancer/teslis antigen I B NM_ 139250
CTAGE4 CTAGE family, member 4 XM_496933
Catenin (cadherin-associated protein), alpha 1 ,
CTNNA 1 NM_001903
102kDa
CTSC Cathepsin C NM_001814
45
2 CTSH Cathepsin H NM_ 148979
Cut-like 1 , CCAAT displacement protein
CUTL1 NM_181500
(Drosophila)
CXCL5 Chemokine (C-X-C motif) ligand 5 N 002994
CYBRD1 Cytochrome b reductase 1 NM 024843
Cytochrome P450, family 2, subfamily R,
CYP2R1 NM_024514 polypeptide 1
Cytochrome P450, family 4, subfamily V,
CYP4V2 NM_207352 polypeptide 2
DBN 1 Drebrin 1 NM 004395
DCA L1 Doublecortin and CaM kinase-like 1 NM 004734
Type 1 transmembrane C-type lectin receptor
DCL- 1 NM_014880
DCL- 1
DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-
DDX3Y NM_004660 linked
DDX58 DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 NM_014314
DDX6 DEAD (Asp-Glu-Ala-Asp) box polypeptide 6 A 021715
DERP6 S-phase 2 protein NM 015362
DIAPH2 Diaphanous homolog 2 (Drosophila) NM_006729
DICER 1 Dicer 1 , Dcr-1 homolog (Drosophila) NM 177438
DIRCl Disrupted in renal carcinoma 1 NM 052952
DJ971 N 18.2 Hypothetical protein DJ971 N 18.2 NM 021 156
DJ971 N18.2 Hypothetical protein DJ971 N 18.2 NM 021 156
D FZp761C 169 Vasculin CR621588
DKK2 Dickkopf homolog 2 (Xenopus laevis) NM 014421
DNCL1 Dynein, cytoplasmic, light polypeptide 1 NM_003746
Deleted in a mouse model of primary ciliary
DPCD AF264625 dyskinesia
DPP3 Dipeptidylpeptidase 3 NM_005700
DREV 1 DORA reverse strand protein 1 NM 016025
Epstein-Barr virus induced gene 2 (lymphocyte-
EBI2 NMJJ04951 specific G protein-coupled receptor)
Enoyl Coenzyme A hydratase domain containing
ECHDC3 NM_024693
3
Extracellular matrix protein 2, female organ and
ECM2 NM_001393 adipocyte specific
Endothelial differentiation, lysophosphatidic acid
EDG4 NM_004720
G-protein-coupled receptor, 4
EGFL3 EGF-like-domain, multiple 3 NM 001409
EHD2 EH-domain containing 2 BC062554
Eukaryolic translation initiation factor 3, subunit
EIF3S3 NM_003756
3 gamma, 40kDa
Eukaryotic translation initiation factor 3, subunit
EIF3S7 NM_003753
7 zeta, 66/67kDa
Eukaryotic translation initiation factor 3, subunit
EIF3S8 NM_003752
8, 1 lOkDa
EIF4B Eukaryotic translation initiation factor 4B NM 001417
ELA1 Elastase 1 , pancreatic NM 001971
E B Embigin homolog (mouse) U52054
EMCN Endomucin AL1331 18
EMILIN2 Elastin microfibril interfacer 2 NM 032048
Egf-like module containing, mucin-like, hormone
EMR2 NMJ 52918 receptor-like 2
Ectonucleotide
ENPP2 NM_006209 pyrophosphatase/phosphodiesterase 2 (autotaxin)
EPB41 L2 Erythrocyte membrane protein band 4.1 -like 2 NM 001431
ES 1 Endothelial cell-specific molecule 1 NM 007036
ESPL1 Extra spindle poles like 1 (S. cerevisiae) NM 012291
46
40-2
Figure imgf000049_0001
Figure imgf000050_0001
48 2
Figure imgf000051_0001
49 -2
Figure imgf000052_0001
50 2 LK2 Kallikrein 2, prostatic NM_005551 RT20 Keratin 20 NMJH9010
LAMB 1 Laminin, beta 1 NM_002291
LAMP2 Lysosomal-associated membrane protein 2 NM_013995
LA R 1 P 15 Laminin receptor 1 pseudogene 15 AF284768
LCP 1 Lymphocyte cytosolic protein 1 (L-plastin) NM_002298
Low density lipoprotein receptor (familial
LDLR M28219 hypercholesterolemia)
LEPR Leptin receptor NM_017526
LEPROTL 1 Leptin receptor overlapping transcript-like 1 AF359269
Lectin, galactoside-binding, soluble, 2 (galectin
LGALS2 NM_006498
2)
Lectin, galactoside-binding, soluble, 8 (galectin
LGALS8 NM_201543
8)
Lectin, galactoside-binding, soluble, 9 (galectin
LGALS9 NM_002308
9)
LHFP Lipoma HMGIC fusion partner NM_005780
Leukocyte immunoglobulin-like receptor,
LILRB2 subfamily B (with T and ITIM domains), NM_005874 member 2
Leukocyte immunoglobulin-like receptor,
LILRB5 subfamily B (with TM and 1T1M domains), NM_006840 member 5
LM02 LIM domain only 2 (rhombotin-like 1 ) NM_005574
LMOD 1 Leiomodin 1 (smooth muscle) AW939148
LMOD1 Leiomodin 1 (smooth muscle) NM 012134
LOCI 14990 Vasorin NM 138440
LOC I 23876 Xenobiotic/medium-chain fatty acid:CoA ligase NM_182617
LOCI 28977 Hypothetical protein LOCI 28977 NM 173793
LOCI 42678 Skeletrophin NM_080875
LOCI 47645 Hypothetical protein LOCI 47645 XM 085831
LOC153561 Hypothetical LOC389295 NM_207331
LOC255458 Hypothetical protein LOC255458 BC009038
LOC283464 Hypothetical protein LOC283464 XM 290597
LOC284323 Hypothetical protein LOC284323 AK091274
LOC339834 Hypothetical protein LOC339834 NM 178173
LOC387680 Similar to KIAA0592 protein NM 001005751
LOC387763 Hypothetical LOC387763 XM 373497
LOC400027 Hypothetical gene supported by BC047417 XM_378350
LOC400581 GRB2-related adaptor protein-like BC026233
Similar to Interferon-induced guanylate-binding
LOC400759 protein 1 (GTP-binding protein 1 ) (Guanine XM_375747 nucleotide-binding protein 1 ) (HuGBP- 1 )
LOC401565 Similar to 4931415M 17 protein NM_001001710
LOC441245 Hypothetical LOC441245 XM_496889
LOC493869 Similar to RIKEN cDNA 2310016C 16 AK0221 10
LOC51035 ORE NM 015853
LOC87769 Hypothetical protein BC004360 XM_373431
LOC 1689 Hypothetical gene supported by AL449243 NM_033318
LPXN Leupaxin NM_00481 1
LRAP Leukocyte-derived arginine aminopeptidase NM_022350
LPS-responsive vesicle trafficking, beach and
LRBA NM_006726 anchor containing
LRRC 14 Leucine rich repeat containing 14 NM 014665
LRRC2 Leucine rich repeat containing 2 NM 024512
LRRIQ2 Leucine-rich repeats and IQ motif containing 2 NM_024548
Latent transforming growth factor beta binding
LTBP4 AF051344 protein 4
5 1
-2
Figure imgf000054_0001
52 -2 Myeloid/lymphoid or mixed-lineage leukemia 5
MLL5 NM_ 182931
(trithorax homolog, Drosophila)
MNS 1 Meiosis-specific nuclear structural protein 1 NM_018365
MOB 1 , Mps One Binder kinase activator-like 2A
MOBKL2A AK024373
(yeast)
MOGAT3 Monoacylglycerol O-acyltransferase 3 NM 178176
MPEG 1 Macrophage expressed gene 1 AK074166
MPP1 Membrane protein, palmitoylated 1 , 55kDa NM 002436
Membrane protein, palmitoylated 2 (MAGUK
MPP2 NM_005374 p55 subfamily member 2)
MPPE1 Metallophosphoesterase 1 NM 138608
Myelin protein zero (Charcot-Marie-Tooth
MPZ NM_000530 neuropathy I B)
MRC1 Mannose receptor, C type 1 NM 002438
MRCL3 Myosin regulatory light chain MRCL3 NM 006471
MRPL43 Mitochondrial ribosomal protein L43 NM 176794
MRPL46 Mitochondrial ribosomal protein L46 NM_022163
Membrane-spanning 4-domains, subfamily A,
MS4A6A NM_022349 member 6A
MSN Moesin NM 002444
Malonyl-CoA:acyl carrier protein transacylase,
MT NM_014507 mitochondrial
MT IA Metallothionein 1 A (functional) NM_005946
MT1E Metallothionein I E (functional) NM 175617
MT1 H Metallothionein 1 H NM_005951
MT U Metallothionein 1J NM 175622
MT1 K Metallothionein I K NM.176870
MT1 L Metallothionein 1 L X97261
MT 1 X Metallothionein IX BC032338
MT 1X Metallothionein I X NM 005952
MT 1X Metallothionein I X NM 005952
MT2A Metallothionein 2A BC007034
MT2A Metallothionein 2A NM_005953
MT2A Metallothionein 2A NM 005953
Membrane-type 1 matrix metalloproteinase
MTCBP- 1 NM_018269 cytoplasmic tail binding protein- 1
MTCH2 Mitochondrial carrier homolog 2 (C. elegans) NM 014342
MTRF1 L Mitochondrial iranslational release factor 1 -like NM 019041
MUC20 Mucin 20 NM_ 152673
MUC3A Mucin 3A, intestinal M55405
Myxovirus (influenza virus) resistance 1 ,
MX1 NM_002462 interferon-inducible protein p78 (mouse)
MY01 B Myosin IB NM 012223
Myocilin, trabecular meshwork inducible
MYOC NM_000261 glucocorticoid response
NAP1 L4 Nucleosome assembly protein 1 -like 4 NM 005969
NC AP1 NCK-associaled protein 1 NM 205842
NFE2L3 Nuclear factor (erythroid-derived 2)-like 3 NM 004289
NFYC Nuclear transcription factor Y, gamma NM_014223
NICN l Nicolin 1 NM 032316
NINJ 1 Ninjurin 1 NM 004148
NIPSNAP3B Nipsnap homolog 3B (C. elegans) NM 018376
NISCH Nischarin NM 007184
NNMT Nicotinamide N-methyltransferase NM_006169
NOL6 Nucleolar protein family 6 (RNA-associated) NM_ 130793
NOSIP Nitric oxide synthase interacting protein NM_015953
NPTX l Neuronal pentraxin I NM 002522
53
-2 Nudix (nucleoside diphosphate linked moiety X)-
NUDT2 NM_001 161 type motif 2
NUP62 Nucleoporin 62kDa NM_ 172374
NXPH4 Neurexophilin 4 NM 007224
NYREN 18 NEDD8 ultimate buster- 1 BC034716
OAS3 2'-5'-oligoadenylate synthetase 3, lOOkDa NM 006187
OAS3 2'-5'-oligoadenylate synthetase 3, lOOkDa NM 006187
Oculocutaneous albinism II (pink-eye dilution
OCA2 NM_000275 homolog, mouse)
OGDHL Oxoglutarate dehydrogenase-like NM 018245
OPLAH 5-oxoprolinase(ATP-hydrolysing) NM 017570
OPRK1 Opioid receptor, kappa 1 NM_000912
OPTN Optineurin NM_021980
OSR2 Odd-skipped related 2 (Drosophila) NM 053001
OSTbeta Organic solute transporter beta NM_178859
P8 P8 protein (candidate of metastasis 1 ) NM_012385
Phosphoprotein associated with
PAG NM_018440 glycosphingolipid-enriched microdomains
PAM Peptidylglycine alpha-amidating monooxygenase NM_000919
PAX 8 Paired box gene 8 A 056052
Pre-B-cell leukemia transcription factor
PBXIP1 NM_020524 interacting protein 1
PCNT2 Pericentrin 2 (kendrin) NM_006031
PCOLCE2 Procollagen C-endopeptidase enhancer 2 NM 013363
PDGFC Platelet derived growth factor C NM_016205
Platelet-derived growth factor receptor, alpha
PDGFRA NM_006206 polypeptide
PDGFRL Platelet-derived growth factor receptor-like NM_006207
PD 4 Pyruvate dehydrogenase kinase, isoenzyme 4 NM_002612
PDZ 1 PDZ domain containing 1 NM 002614
PERLD 1 Perl-like domain containing 1 NM 033419
PEX 19 Peroxisomal biogenesis factor 19 NM 002857
PG 1 Phosphoglucomutase 1 NM_O02633
PGRMCl Progesterone receptor membrane component 1 NM_006667
RNA U, small nuclear RNA export adaptor
PHAX AF086448
(phosphorylation regulated)
PHCA Phytoceramidase, alkaline NM 018367
PIP Prolactin-induced protein NM_002652
Phosphatidylinositol transfer protein, cytoplasmic
PITPNC1 NM_012417
1
P 2 Pyruvate kinase, muscle NM 182471
P P2 Plakophilin 2 X97675
PLAU Plasminogen activator, urokinase NM_002658
PMP22 Peripheral myelin protein 22 NM 000304
PNPLA4 Patatin-like phospholipase domain containing 4 NM_004650
POLD4 Polymerase (DNA-directed), delta 4 NM 021 173
Polymerase (RNA) II (DNA directed)
POLR2L NM_021 128 polypeptide L, 7.6kDa
POU2F1 POU domain, class 2, transcription factor 1 S66901
PP3856 Similar to CG3714 gene product NM_ 145201
PPAP2B Phosphatidic acid phosphatase type 2B NM 003713
Protein tyrosine phosphatase, receptor type, f
PPFIA4 polypeptide (PTPRF), interacting protein (liprin), NM_015053 alpha 4
PPIC Peptidylprolyl isomerase C (cyclophilin C) NM 000943
PPIC Peptidylprolyl isomerase C (cyclophilin C) NM 000943
PPIL3 Peptidylprolyl isomerase (cyclophilin)-like 3 NM_131916
54
-2 Protein phosphatase I F (PP2C domain
PPM IF NM_014634 containing)
PRAC Small nuclear protein PRAC NM_032391
PREB Prolactin regulatory element binding BE395450
Peroxisomal proliferator-activated receptor A
PRIC285 NM_033405 interacting complex 285
PRKD2 Protein kinase D2 NM_016457
PR Y Protein kinase, Y-linked NM 002760
PRSS 15 Protease, serine, 15 NM 004793
Proteasome (prosome, macropain) subunit, alpha
PSMA5 NM_002790 type, 5
Proteasome (prosome, macropain) subunit, beta
PSMB9 NM_ 148954 type, 9 (large multifunctional protease 2)
Proteasome (prosome, macropain) 26S subunit,
PSMD1 1 . NM_002815 non-ATPase, 1 1
PSORS 1C1 Psoriasis susceptibility 1 candidate 1 NM_014068
PSPH Phosphoserine phosphatase NM 004577
PSPHL Phosphoserine phosphatase-like AJ001612
PTAFR Platelet-activating factor receptor S52624
PTGIS Prostaglandin 12 (prostacyclin) synthase NM_000961
PTOV 1 Prostate tumor overexpressed gene 1 NM 017432
PTP4A3 Protein tyrosine phosphatase type IVA, member 3 NM_0O7O79
PTPRC Protein tyrosine phosphatase, receptor type, C NM_080922
Poliovirus receptor-related 2 (herpesvirus entry
PVRL2 NM_002856 mediator B)
PXMP2 Peroxisomal membrane protein 2, 22kDa NM_018663
R30953_l Interferon inducible GTPase 5 NM_019612
RAB 15 RAB 15, member RAS onocogene family NM_ 198686
Rabaptin, RAB GTPase binding effector protein
RABEP 1 NM_004703
1
Ras-related C3 botulinum toxin substrate 2 (rho
RAC2 NM_002872 family, small GTP binding protein Rac2)
Ras-related C3 botulinum toxin substrate 2 (rho
RAC2 NM_002872 family, small GTP binding protein Rac2)
RAD51AP1 RAD51 associated protein 1 NM 006479
RAI16 Retinoic acid induced 16 NM 022749
Ras association (RalGDS/AF-6) and pleckstrin
RAPH1 NM_213589 homology domains 1
Reversion-inducing-cysteine-rich protein with
RECK NM_021 1 1 1 kazal motifs
Ral guanine nucleotide dissociation stimulator¬
RGL2 NM_004761 like 2
RGS 10 Regulator of G-protein signalling 10 NM 001005339
RGS 1 1 Regulator of G-protein signalling 1 1 BC040504
RGS 16 Regulator of G-protein signalling 16 NM_002928
RGS5 Regulator of G-protein signalling 5 NM_003617
RHBDF1 Rhomboid family 1 (Drosophila) NM_022450
RHOT2 Ras homolog gene family, member T2 NM 138769
RIMS3 Regulating synaptic membrane exocytosis 3 NM_014747
RIP RPA interacting protein NM_032308
RIPK2 Receptor-interacting serine-threonine kinase 2 NM_003821
RLN3 Relaxin 3 NM 080864
RNASE4 Angiogenin, ribonuclease, RNase A family, 5 NM 001 145
RNASE4 Angiogenin, ribonuclease, RNase A family, 5 NM_194431
RNF121 Ring finger protein 121 AK023139.
RNF125 Ring finger protein 125 NM_017831
RNF13 Ring finger protein 13 NM 007282
R FI 38P1 Ring finger protein 138 pseudogene 1 AW975013
55
-2 RNF146 Ring Finger protein 146 NM 030963
RNF19 Ring Finger protein 19 NM 183419
Roundabout, axon guidance receptor, homolog 1
ROBOl NM_002941
(Drosophila)
Roundabout, axon guidance receptor, homolog 3
ROB03 NM_022370
(Drosophila)
RPL10A Ribosomal protein LlOa NM_007104
RPL41 Ribosomal protein L41 NM 021 104
RPL7A Ribosomal protein L7a NM 000972
RPS 10 Ribosomal protein S 10 NM 001014
RPS 16 Ribosomal protein S 16 NM_001020
RPS 18 Ribosomal protein S 18 NM 022551
RPS4X Ribosomal protein S4, X-linked NM 001007
RPS4Y 1 Ribosomal protein S4, Y-linked 1 NM 001008
RPS4Y2 Ribosomal protein S4, Y-linked 2 NM.138963
RRAGD Ras-related GTP binding D NM_021244
Radical S-adenosyl methionine and flavodoxin
RSAFD 1 NM_018264 domains 1
RTN4 Reticulon 4 NM 153828
RUTBC3 RUN and TBC 1 domain containing 3 NM_015705
S I OOP S 100 calcium binding protein P NM 005980
S AMD 10 Sterile alpha motif domain containing 10 NM_080621
SARA1 SARI a gene homolog 1 (S. cerevisiae) NM 020150
SARA 1 SARI a gene homolog 1 (S. cerevisiae) NM_020150
SAT Spermidine/spermine N 1 -acetyltransferase NM 002970
SAV 1 Salvador homolog 1 (Drosophila) NM_021818
SCAP SREBP CLEAVAGE-ACTIVATING PROTEIN NM 012235
SCGB 1 D 1 Secretoglobin, family I D, member 1 NM_006552
SCGB2A 1 Secretoglobin, family 2A, member 1 NM_002407
SCUBE3 Signal peptide, CUB domain, EGF-like 3 NM_ 152753
SD 1 Sidekick homolog 1 (chicken) AF052150
SECP43 TRNA selenocysteine associated protein NM_017846
SECTM 1 Secreted and transmembrane 1 NM_003004
Sema domain, immunoglobulin domain (Ig),
SEMA3B NM_004636 short basic domain, secreted, (semaphorin) 3B
Serine (or cysteine) proteinase inhibitor, clade B
SERPINB2 B CO 12609
(ovalbumin), member 2
SESN 1 Sestrin 1 NM 014454
SESN2 Sestrin 2 NM_031459
SF4 Splicing factor 4 NM_ 172231
Sarcoglycan, alpha (50kDa dystrophin-associated
SGCA NM_000023 glycoprotein)
SH3 domain binding glutamic acid-rich protein
SH3BGRL NM_003022 like
SH3GLB 1 SH3-domain GRB2-like endophilin B 1 NM 016009
SH3GLB2 SH3-domain GRB2-like endophilin B2 NM_020145
SH3RF2 SH3 domain containing ring Finger 2 NM 152550
ShrmL Shroom-related protein NM 020859
SIRPB2 Signal-regulatory protein beta 2 NM 018556
SLAMF9 SLAM family member 9 NM 033438
Solute carrier family 10 (sodium/bile acid
SLC 10A3 NM_019848 cotransporter family), member 3
Solute carrier family 12
SLC 12A2 (sodium/potassium/chloride transporters), NM_001046 member 2
Solute carrier family 12 (potassium chloride
SLC 12A9 NM_020246 transporters), member 9
56
2 Solute carrier family 14 (urea transporter),
SLC 14A1 L36121 member 1 (Kidd blood group)
Solute carrier family 20 (phosphate transporter),
SLC20A1 NM_005415 member 1
Solute carrier family 39 (zinc transporter),
SLC39A 14 BC000068 member 14
Solute carrier family 6 (neurotransmitter
SLC6A 15 NM_018057 transporter), member 15
Solute carrier family 7 (cationic amino acid
SLC7A 1 NM_003045 transporter, y+ system), member 1
Solute carrier family 7 (cationic amino acid
SLC7A7 NM_003982 transporter, y+ system), member 7
Solute carrier family 9 (sodium/hydrogen
SLC9A3R2 NM_004785 exchanger), isoform 3 regulator 2
Solute carrier family 9 (sodium/hydrogen
SLC9A9 NMJ73653 exchanger), isoform 9
Solute carrier organic anion transporter family,
SLC02B 1 NM_007256 member 2B 1
Secretory leukocyte protease inhibitor
SLPI NM_003064
(antileukoproteinase)
Secretory leukocyte protease inhibitor
SLPI NM_003064
(antileukoproteinase)
SMAD, mothers against DPP homolog 1
SMAD1 NM_005900
(Drosophila)
SMAP1 Stromal membrane-associated protein 1 NM_021940
SWI/SNF related, matrix associated, actin
SMARCA4 dependent regulator of chromatin, subfamily a, NM_003072 member 4
SWI/SNF related, matrix associated, actin
SMARCE 1 dependent regulator of chromatin, subfamily e, NM_003079 member 1
SMC5 structural maintenance of chromosomes 5-
SMC5L1 NM_015110 like 1 (yeast)
SMN2 Survival of motor neuron 1 , telomeric N _022877
SMP1 NPD014 protein NM_014313
SMTN Smoothelin NM_ 134269
SNTG2 Syntrophin, gamma 2 NM_018968
SNX7 Sorting nexin 7 NM_015976
SOCS5 Suppressor of cytokine signaling 5 NM_01401 1
SORD Sorbitol dehydrogenase NM 003104
SP 1 Sp l transcription factor NM_ 138473
Secreted protein, acidic, cysteine-rich
SPARC NM_0031 18
(osteonectin)
SRD5A2L Steroid 5 alpha-reductase 2-like NM_024592
SRGAP3 SLIT-ROBO Rho GTPase activating protein 3 AF086321
SRP 2 SFRS protein kinase 2 NM_ 182691
SPRY domain-containing SOCS box protein
SSB3 NM_080861
SSB-3
SSPN Sarcospan (Kras oncogene-associated gene) NM 005086
Signal transducer and activator of transcription 6,
STAT6 NM_003153 interleukin-4 induced
STX7 Syntaxin 7 NM 003569
SULF1 Sulfatase 1 NM 015170
SUMF1 Sulfatase modifying factor 1 NM 182760
Synapse associated protein 1 , SAP47 homolog
SYAP1 NM_032796
(Drosophila)
SYMP Symplekin NM 004819
SYNGR2 Synaptogyrin 2 NM_004710
57
-2
Figure imgf000060_0001
58 -2 UBE2V I Ubiquitin-conjugating enzyme E2 variant 1 NM 199144
Ubiquitin protein ligase E3A (human papilloma
UBE3A virus E6-associated protein, Angelman AF037219 syndrome)
UBL3 Ubiquitin-like 3 NM 007106
UHS erB Keratin, ultrahigh sulfur, B NM 021046
UL 2 Unc-51 -like kinase 2 (C. elegans) NM_014683
URB Steroid sensitive gene 1 NM 19951 1
USP54 Ubiquitin specific protease 54 NM_152586'
UST Uronyl-2-sulfoiransferase NM_0057 15
UTRN Utrophin (homologous to dystrophin) AK023675
Ubiquitously transcribed tetratricopeptide repeal,
UTX NM_02 i 140
X chromosome
VARS2L Valyl-tRNA synthetase 2-like NM_020442
VAV 1 Vav 1 oncogene NM_005428
VGLL4 Vestigial like 4 (Drosophila) BQ013066
VN1 R1 Vomeronasal 1 receptor 1 NM 020633
VSIG4 V-set and immunoglobulin domain containing 4 NM_007268
WDR22 WD repeat domain 22 NM_003861
WIF1 WNT inhibitory factor 1 NM_007191
WWOX WW domain containing oxidoreductase AK094336
Xg blood group (pseudoautosomal boundary-
XG NM_175569 divided on the X chromosome)
XIST X (inactive)-specific transcript AK025198
XYLT2 Xylosyltransferase 11 NM 022167
YPEL5 Yippee-like 5 (Drosophila) NM 016061
ZBTB7 Zinc finger and BTB domain containing 7 NM_015898
ZFHX 1 B Zinc finger homeobox l b NM 014795
ZFYVE26 Zinc finger, FYVE domain containing 26 NM_015346
ZNF516 Zinc Finger protein 516 D86975
ZNF552 Zinc finger protein 552 AK023769
ZNF572 Zinc finger protein 572 NM 152412
ZP3 Zona pellucida glycoprotein 3 (sperm receptor) NM 007155
ZSCAN2 Zinc finger and SCAN domain containing 2 NM 017894
No Annotation A_23_BS 1 13762
No Annotation A 24 BS784213
No Annotation A_24_BS926155
No Annotation A 24 BS927614
No Annotation A_24_BS934268
No Annotation A 32 BS 169243
No Annotation A 32 BS200773
No Annotation A_32_BS53976
No Annotation A 32 BS73 184
No Annotation A_32_BS74588
No Annotation AB065507
No Annotation AC007051
No Annotation AC007066
No Annotation AC008453
No Annotation AC025463
No Annotation AC060234
No Annotation AC087071
No Annotation AC096677
Full length insert cDNA clone ZB81 F12 AF086167
No Annotation AF089746
Amyloid lambda 6 light chain variable region
AF121762 SAR
59
2 IMAGE Consortium ID 839832, mRNA
AF124368 sequence
Clone FLB4246 PROl 102 mRNA, complete cds AF130105
HSPC 101 AF161364
LOC440135 AF318337
No Annotation AF372624
No Annotation AF533936
MRNA (fetal brain cDNA g6_lg) AI791206
Hypothetical protein (ORF1), clone 00275 AJ276555
No Annotation A 001565
Hypothetical LOC388796 A 022745
Homo sapiens, clone IMAGE:4401608, mRNA AK022793
Homo sapiens, clone IMAGE:42143 13, mRNA AK022893
Homo sapiens, clone IMAGE:5277945, mRNA A 022997
CDNA: FLJ22769 fis, clone KAIA 1316 A 026422
CDNA FLJ31059 fis, clone HSYRA2000832 A 055621
CDNA FLJ32177 fis, clone PLACE6001294 AK056856
Homo sapiens, clone IMAGE:5575764, mRNA A 090500
Homo sapiens, clone IMAGE:5575764, mRNA AK092921
CDNA FLJ36725 Fis, clone UTERU2012230 A 094044
CDNA FLJ38235 fis, clone FCBBF2005428 A 095554
CDNA FLJ25794 fis, clone TST07014 AK098660
No Annotation AL009178
MRNA; cDNA D FZp566L0824 (from clone
AL050042 DKFZp566L0824)
No Annotation AL109935
No Annotation AL132874
Full-length cDNA clone CS0DJ001 YJ05 of T
cells (Jurkat cell line) Cot 10-normalized of AL137761 Homo sapiens (human)
No Annotation AL391244
No Annotation AL445486
No Annotation AL591806
No Annotation AL731541
No Annotation AL928970
No Annotation AY062331
No Annotation AY372690
No Annotation BC009051
LOC441 164 BC009220
CDNA clone IMAGE:3462401 , partial cds BC010544
No Annotation BC01 1367
No Annotation BC015531
LOC440441 BC020847
Homo sapiens, clone. IMAGE:5295565, mRNA,
BC031278 partial cds
Similar to jumonji domain containing 1 A; lestis-
BC035 I02 specific protein A; zinc finger protein
Homo sapiens, clone IMAGE:5575764, mRNA BC035647
Hypothetical LOCI 7387 BC038761
Hypothetical gene supported by BC039664 BC039664
No Annotation BC 107852
No Annotation BG252130
Full-length cDNA clone CS0DI009YA14 of
Placenta Cot 25-normalized of Homo sapiens BG327427 (human)
Hypothetical LOC339352 BG620990 Similar to PI-3-kinase-related kinase SMG- 1
isoform 2; lambda/iota protein kinase C-
. BI014689 interacting protein; phosphatidylinositol 3-kinase- related protein kinase
Similar to D(1 B) dopamine receptor (D(5)
BM561346 dopamine receptor) (D lbeta dopamine receptor)
No Annotation BM839360
Transcribed locus BM925639
No Annotation BM928667
Transcribed locus BQ049338
No Annotation BQ346290
Homo sapiens, clone IMAGE:4838137, mRNA BU587941
LOC441 139 BX 1 18328
No Annotation D80006
No Annotation DQ101 103
No Annotation DQ188807
No Annotation ENST00000242479
No Annotation ENST00000246627
No Annotation ENST00000259219
No Annotation ENSTOO00O25955O
No Annotation ENST00O0O293569
No Annotation ENST00000296448
No Annotation ENST00000298643
No Annotation ENST00000299756
No Annotation ENST0OO0O3O0O68
No Annotation ENST00000305402
No Annotation ENST00000305824
No Annotation ENST00000307901
No Annotation ENST0OOOO3O83O7
No Annotation ENST000003 10210
No Annotation ENST000003 12401
No Annotation ENST00000312412
No Annotation ENST000003 12966
No Annotation ENST00000313904
No Annotation ENST00000318669
No Annotation ENST0O0O0321 1 12
No Annotation ENST00000321656
No Annotation ENST000003221 14
No Annotation ENST00000322404
No Annotation ENST00000322803
No Annotation ENST00000324770
No Annotation ENST00000325204
No Annotation ENSTOO0O0325773
No Annotation ENST00000327591
No Annotation ENST00000327870
No Annotation ENST00000328059
No Annotation ENST00000328708
No Annotation ENST00000329246
No Annotation ENST00000329358
No Annotation ENST00000329491
No Annotation ENST00000329660
No Annotation ENSTO0OOO330875
No Annotation ENSTO0O0O331096
No Annotation ENST00000331577
No Annotation ENST00000331640
No Annotation ENST00000332271
No Annotation ENST00000332944 No Annotation ENST00000332989
No Annotation ENST00000333517
No Annotation ENST00000333784
Transcribed locus, weakly similar to
NP_808455. 1 hypothetical prolein 9830102E05 H I 6080 [ us musculus]
No Annotation I_ 1000437
No Annotation LI 100650
No Annotation I_ 1221777
No Annotation LI 861543
No Annotation I_l 879042
No Annotation · L 1882608
No Annotation L1891291
No Annotation L1893151
No Annotation L 1980505
No Annotation L1985061
No Annotation L3335767
No Annotation L3344109
No Annotation L355 1568
No Annotation L3575384
No Annotation L3576071
No Annotation L3580313
No Annotation L3588329
No Annotation L930906
No Annotation L932413
No Annotation L943866
No Annotation L944092
No Annotation L962800
No Annotation I 964340
No Annotation L966091
No Annotation L966691
No Annotation M l 5073
No Annotation M64260
No Annotation NG 001019
No Annotation NM_001005360
No Annotation NM_001008528
No Annotation NM_001009555
No Annotation NM_001009569
No Annotation NMJXM010919
No Annotation NMJXM01 1708
No Annotation NM_001013632
No Annotation NM_001013680
No Annotation NM_001014975
No Annotation NM_001018006
No Annotation NM_00101801 1
No Annotation NM_001018076
No Annotation NM_001024227
No Annotation NM_001024465
No Annotation NM_001024808
No Annotation NM_001025077
No Annotation NM_001025201
No Annotation NM_00103 1677
No Annotation NM_001033044
No Annotation NM_001033569
No Annotation NM 003671
No Annotation NM_014758
No Annotation NM 015262 No Annotation NM 018350
No Annotation NM 018506
No Annotation NM_080432
No Annotation NM_13841 1
No Annotation NM 153030
No Annotation NM_153237
No Annotation NM_ 172020
No Annotation NM 173705
No Annotation NM_ 173709
No Annotation NM_ 178429
No Annotation NM 178467
No Annotation NM 213595
No Annotation NR 001544
No Annotation NR_002184
No Annotation NR_002225
Anti-HIV-1 gpl20 V3 loop antibody DO 142- 10
S62210 light chain variable region
No Annotation S 80864
No Annotation THC 1409898
No Annotation THC1419743
No Annotation THC 1429821
No Annotation THC 1434038
No Annotation THC 1438453
No Annotation THC 1441583
No Annotation THC 1448600
No Annotation THC 1457058
No Annotation THC 1457 1 18
No Annotation THC 1459712
No Annotation THC 1461073
No Annotation THC 1469536
No Annotation THC 1475763
No Annotation THC 1477639
No Annotation THC 1484458
No Annotation THC 1490378
No Annotation THC 1493219
No Annotation THC 1504780
No Annotation THC 1505917
No Annotation THC 1506312
No Annotation THC 151 1927
No Annotation THC1515028
No Annotation THC1525318
No Annotation THC 1531579
No Annotation THC 1537 124
No Annotation THC 1543691
No Annotation THC 1544941
No Annotation THC 1551463
No Annotation THC 1555359
No Annotation THC 1559236 No Annotation THC 1560798
No Annotation THC 1562602
No Annotation THC 1563147
No Annotation THC 1564329
No Annotation THC 1572906
No Annotation THC 1572972
No Annotation THC 1574967
No Annotation THC 1578318
No Annotation THC 1581022 No Annotation THC 1584122
No Annotation THC 1589164
No Annotation THC 1591470
Hypothetical gene LOC I 33874 U31733
No Annotation U62539
No Annotation X68990
No Annotation XM 065006
No Annotation XM 165930
No Annotation XM_17021 1
Similar to ARHQ protein X _209429
No Annotation XM 210579
No Annotation XM 291496
No Annotation XM_291718
No Annotation XM 295760
No Annotation XM_301448
No Annotation XM 303638
No Annotation XM_305652
Similar to Tubulin beta-4q chain XM_371684
Similar to CXYorfl -related protein XM_377073
Similar to immunoglobulin M chain Y l 1328
Example 3: Use of Linear Discriminant Analysis (LDA) to Distinguish the Diffuse- Proliferation and Inflammatory Groups.
Genes that distinguished samples in the Diffuse-Proliferation and Inflammatory groups were selected using Linear Discriminant Analysis (LDA), described in Example 2, and the initial skin biopsy gene expression datasets. Examination of the expression data for single genes shows that the expression any one single gene may not always clearly distinguish between the groups of proliferation and no proliferation. In contrast, the multivariable LDA analysis results in LDA scores that separated the two groups more than by using the gene expression of single genes alone. Particularly in the case of testing the results of the LDA equation for the Inflammatory group in a separate dataset, the multivariate analysis resulted in clear separation of the two groups. This analysis therefore provides potential biomarkers in the skin for identifying the intrinsic subsets in SSc in new skin biopsies.
For the Diffuse-Proliferation group, LDA Score =
- 1.902(NM_004703) - 1.908(NM_020422) + 1.475(AGI_HUM 1_OLIGO_A_24_P690235) + 1.83(NM_17351 1), where NM_004703 corresponds to RABEP 1 , NM_020422 corresponds to promethin, AGI_HUM 1_OLIGO_A_24_P690235 refers to novel gene transcript
ENST00000312412, and NM_17351 1 refers to ALS2CR 13.
For the Inflammatory group, LDA score = 4.365(NM_0021 19) + 2.926(NM_006851) - 2.620(NM_017570) + 6.601 (NM_022163) + 2.033(NM_0121 10), where NM_0021 19 refers to HLA-DOA, NM_006851 refers to GLIPR 1 , NM_017570 refers to OPLAH,
64
2613340-2 NM_022163 refers to MRPL46, and NM_0121 10 refers to CHIC2.
Example 4: IL-13 and IL-4 Gene Signatures Identify the Inflammatory Subset
In addition to TGFp, gene expression signatures associated with pro-fibrotic cytokines IL- 13 (NM_002188) and IL-4 (NM_000589) were determined in cultured adult human dermal fibroblasts. The 490 genes of the IL- 13 gene signature are presented in Table 4. The genes of the IL-4 gene signature are presented in Table 5. This analysis indicated that IL- 13 and IL-4 share an approximately 60% overlap of inducible genes. In contrast, the TGFp inducible signature was composed of a distinct set of gene expression targets demonstrating a 5% overlap with the IL- 13 and IL-4 signatures.
Gene expression signatures were used to determine the potential drivers of fibrosis in a large well-controlled gene expression dataset of SSc skin biopsies, which were demonstrated herein as molecular subsets in scleroderma skin. The TGFp signature was largely expressed in a subset of diffuse patients and was more highly expressed in patients with more severe skin disease (p < 0.01 ) and scleroderma lung disease (p < 0.01 ). The IL- 13 and IL-4 gene expression signatures showed increased expression in the Inflammatory subset of SSc patients biopsies, and represent the earliest disease stages.
It is contemplated that fibrosis in different SSc subsets is driven by different molecular mechanisms tied to either TGFp or IL- 13 and IL-4. These finding indicate that patient subsetting is necessary in order to target different anti-fibrotic treatments based on molecular subclassifications of SSc patients.
TABLE 4
Figure imgf000067_0001
65
2613340-2 APOH Apolipoprotein H (beia-2-glycoprotein I) N _000042
ARHGAP18 Rho GTPase activating protein 18 NM 033515
ARHGDIB Rho GDP dissociation inhibitor (GDI) beta NM 001 175
ARNT2 Aryl-hydrocarbon receptor nuclear translocator 2 NM 014862
ARRDC4 Arrestin domain containing 4 NM_ 183376
ASB9 Ankyrin repeat and SOCS box-containing 9 NM_024087
ASCL2 Achaete-scute complex-like 2 (Drosophila) NM 005170
ASPA Aspartoacylase (aminoacylase 2, Canavan disease) NM_000049
ASPM Asp (abnormal spindle)-like, microcephaly associated NM_018136
(Drosophila)
ASPM Asp (abnormal spindle)-like, microcephaly associated NM_018136
(Drosophila)
ATF3 Activating transcription factor 3 NM_004024
ATF7I 2 Activating transcription factor 7 interacting protein 2 CR626222
BCL! I A B-cell CLL/lymphoma 1 1 A (zinc finger protein) BU540282
BD RB 1 Bradykinin receptor B 1 NM 000710
BD RB 1 Bradykinin receptor B 1 NM 000710
BD RB2 Bradykinin receptor B2 NM 000623
BIRC5 Baculoviral 1AP repeat-containing 5 (survivin) BC007606
BNC 1 Basonuclin 1 NM_0017 17
BNC2 Basonuclin 2 BC020879
BNC2 Basonuclin 2 NM 017637
BNC2 Basonuclin 2 NM 017637
BSPRY B-box and SPRY domain containing NM_017688
BUB 1 BUB 1 budding uninhibited by benzimidazoles 1 NM_004336 homolog (yeast)
ClOorflO Chromosome 10 open reading frame 10 NM 007021
ClOorO ■ Chromosome 10 open reading frame 3 NM_018131
C10orf72 Chromosome 10 open reading frame 72 AK001062
C! 3orO Chromosome 13 open reading frame 3 BC013418
C18orfl l Chromosome 18 open reading frame 1 1 NM 022751
C18orfl 1 Chromosome 18 open reading frame 1 1 NM_022751
C18orf4 Chromosome 18 open reading frame 4 NM_032160
C20orfl 29 Chromosome 20 open reading frame 129 NM_030919
C21 orf81 Chromosome 21 open reading frame 81 NM 153750
C4BPA Complement component 4 binding protein, alpha NM_000715
C5orfl 3 Chromosome 5 open reading frame 13 NM_004772
C5orf4 Chromosome 5 open reading frame 4 NM 032385
C8orf22 Chromosome 8 open reading frame 22 NM 001007176
C9orf58 Chromosome 9 open reading frame 58 NM 001002260
C9orf58 Chromosome 9 open reading frame 58 NM_001002260
CA8 Carbonic anhydrase VIII NM 004056
CAV 1 Caveolin 1 , caveolae protein, 22kDa NM 001753
CAV 1 Caveolin 1 , caveolae protein, 22kDa NM 001753
CCL2 Chemokine (C-C motif) ligand 2 NM 002982
CCL26 Chemokine (C-C motif) ligand 26 NM_006072
CCNB 1 Cyclin B l NM 031966
CCNB2 Cyclin B2 NM 004701
CCR1 Chemokine (C-C motif) receptor 1 NM 001295
CCRL1 Chemokine (C-C motif) receptor-like 1 NM 178445
CD200 CD200 antigen NM 001004196
CD33 CD33 antigen (gp67) NM_001772
CD38 CD38 antigen (p45) NM 001775
CD3G CD3G antigen, gamma polypeptide (TiT3 complex) NM 000073
CDC2 Cell division cycle 2, G l to S and G2 to M NM 001786
CDC20 CDC20 cell division cycle 20 homolog (S. cerevisiae) NM 001255
CDC25C Cell division cycle 25C NM_00I 790
66
2613340-2 CDC37L1 Cell division cycle 37 homolog (S. cerevisiae)-like 1 NM_017913 ·
CDCA2 Cell division cycle associated 2 NM 152562
CDCA5 Cell division cycle associated 5 NM_080668
CDCA8 Cell division cycle associated 8 NM_018101
CDH 1 Cadherin 1 , type 1 , E-cadherin (epithelial) NM 004360
CDH 18 Cadherin 18, type 2 NM_004934
CDKN3 Cyclin-dependent kinase inhibitor 3 (CDK2-associated NM_005192 dual specificity phosphatase)
CEACAM 1 Carcinoembryonic antigen-related cell adhesion NM_001712 molecule 1 (biliary glycoprotein)
CENPF Centromere protein F, 350/400ka (mitosin) NM 016343
CGA Glycoprotein hormones, alpha polypeptide NM_O0O735
CH25H Cholesterol 25-hydroxylase NM 003956
CHST6 Carbohydrate (N-acetylglucosamine 6-0) NM_021615 sulfotransferase 6
CISH Cytokine inducible SH2-containing protein NM 145071
CITED4 Cbp/p300-interacting transactivator, with Glu/Asp-rich NM_133467 carboxy-terminal domain, 4
CKLFSF8 Chemokine-like factor super family 8 NM_178868
CLDN ! l Claudin 1 1 (oligodendrocyte transmembrane protein) AF085871
CMKOR1 Chemokine orphan receptor 1 NM_02031 1
CNIH3 Cornichon homolog 3 (Drosophila) NM 152495
COL4A6 Collagen, type IV, alpha 6 NM_033641
COL8A2 Collagen, type VIII, alpha 2 NM_005202
CP Ceruloplasmin (ferroxidase) NM 000096
CPB2 Carboxypeptidase B2 (plasma, carboxypeptidase U) NM_001872
CPXM2 Carboxypeptidase X (M l 4 family), member 2 NM_198148
CTGF Connective tissue growth factor NM_001901
CTNNALl Catenin (cadherin-associated protein), alpha-like 1 NM 003798
CX3CL1 Chemokine (C-X3-C motif) ligand 1 NM_002996
CX3CR1 Chemokine (C-X3-C motif) receptor 1 NM_001337
CXCL1 Chemokine (C-X-C motif) ligand 1 (melanoma growth NM_00151 1 stimulating activity, alpha)
CXCL14 Chemokine (C-X-C motif) ligand 14 NM_004887
CXCR4 chemokine (C-X-C motif) receptor 4 NM_001008540
CYP2F1 Cytochrome P450, family 2, subfamily F, polypeptide 1 NM_000774
DCAMKL1 Doublecortin and CaM kinase-like 1 NM_004734
DCN Decorin BQ004014
D FZP434B061 DKFZP434B061 protein AL1 17481
DKFZP434I216 D FZP434I216 protein NM 015432
D FZp564I 1922 Adlican NM_015419
D FZP586A0522 DKFZP586A0522 protein NM 014033
DKFZP586A0522 DKFZP586A0522 protein NM_014033
DKFZP586 1520 D FZP586K I520 protein AL050I 53
DLG7 Discs, large homolog 7 (Drosophila) NM_014750
DMD Dystrophin (muscular dystrophy, Duchenne and Becker NM_004010 types)
DO 1 Docking protein 1 , 62kDa (downstream of tyrosine NM_001381 kinase 1 )
DRCTNNB 1 A Down-regulated by Ctnnb 1 , a NM_032581
DUSP6 Dual specificity phosphatase 6 NM_00I946
ECHDC3 Enoyl Coenzyme A hydratase domain containing 3 NM_024693
ECM2 Extracellular matrix protein 2, female organ and NM_001393 adipocyte specific
ED 1 Endothelin 1 NM 001955
EFNB2 Ephrin-B2 NM 004093
EGLN3 Egl nine homolog 3 (C. elegans) NM_022073
67
2613340-2 EGR 1 Early growth response 1 NM_001964
EN 1 Engrailed homolog 1 NM 001426
ENC 1 Ectodermal-neural cortex (with BTB-like domain) NM 003633
ENC1 Ectodermal-neural cortex (with BTB-like domain) NM 003633
EPHA4 EPH receptor A4 NM 004438
EPHX2 Epoxide hydrolase 2, cytoplasmic NM_001 79
EXOSC8 Exosome component 8 NM 181503
EXOSC8 Exosome component 8 NM 181503
FAB PI Fatty acid binding protein 1 , liver NM 001443
FADS 1 Fatty acid desaturase 1 NM_013402
FBX032 F-box protein 32 NM_058229
FCGR2A Fc fragment of IgG, low affinity Ila, receptor for NM_021642
(CD32)
FGF7 Galactokinase 2 NM_002009
FGF7 Galactokinase 2 NM 002009
FGF7 Galactokinase 2 NM_002009
FHL2 Four and a half LIM domains 2 NM_201555
F SG 14 Leucine zipper protein F SG 14 NM_022145
FLJ 10156 Hypothetical protein FLJ 10156 NM_019013
FLJ 13391 Hypothetical protein FLJ 13391 NM 032181
FLJ 14712 Hypothetical protein FLJ 14712 A 027618
FLJ20255 Hypothetical protein FLJ20255 A 000262
FLJ31340 Hypothetical protein FLJ31340 NM 152748
FLJ35767 FLJ35767 protein NM 207459
FLJ36031 Hypothetical protein FLJ3603 1 A 098422
FLJ36031 Hypothetical protein FLJ3603 1 NM 175884
FLJ37478 Hypothetical protein FLJ37478 NM_178557
FLJ40629 Hypothetical protein FLJ40629 NMJ 52515
F N Formin (limb deformity) BC029107
F0XQ 1 Forkhead box Ql NM_033260
FZD 10 Frizzled homolog 10 (Drosophila) NM 007197
FZD4 Frizzled homolog 4 (Drosophila) NM_012193
G2 G2 protein U 10991
GAL Galanin NM 015973
GAS 1 Growth arrest-specific 1 NM_002048
GATA6 GATA binding protein 6 NM 005257
GDF3 Growth differentiation factor 3 NM 020634
GEM GTP binding protein overexpressed in skeletal muscle NM 005261
GLCCI1 Glucocorticoid induced transcript 1 NM 138426
GNG 1 1 Guanine nucleotide binding protein (G protein), gamma NM_004126
1 1
GPR68 G protein-coupled receptor 68 NM 003485
GREM 1 Gremlin 1 homolog, cysteine knot superfamily NM_013372
(Xenopus laevis)
GSG 1 Germ cell associated 1 NM 031289
GTS El G-2 and S-phase expressed 1 NM_016426
HAS3 Hyaluronan synthase 3 NM 005329
HCAP-G Chromosome condensation protein G NM 022346
HES 1 Hairy and enhancer of split 1 , (Drosophila) NM 005524
H1ST 1H4B •Histone 1 , H4b NM 003544
H1ST1H4C Histone 1 , H4c NM 003542
HIST1 H4L Histone 1 , H4I NM 003546
HLF Hepatic leukemia factor NM 002126
HMMR Hyaluronan-mediated motility receptor (RHAMM) NM 012484
HRH 1 Histamine receptor H I NM 000861
HT008 Uncharacterized hypothalamus protein HT008 NM 018469
ICA1 Islet cell autoantigen 1 , 69kDa NM 004968
68
2613340-2 ICAM5 Intercellular adhesion molecule 5, telencephalin NM 003259
ID1 Inhibitor of DNA binding 1 , dominant negative helix- NM_002165 loop-helix protein
IFI44 Interferon-induced protein 44 NM_006417
IL6 Interleukin 6 (interferon, beta 2) NM_000600
INSIG2 Insulin induced gene 2 NM_016133
INSIG2 Insulin induced gene 2 NM_016 I33
IRF5 Interferon regulatory factor 5 NM_002200
JAG 1 Jagged 1 (Alagille syndrome) NM_000214
KCNH2 Potassium voltage-gated channel, subfamily H (eag- NM_000238 related), member 2
KCNMB4 Potassium large conductance calcium-activated NM_014505 channel, subfamily M, beta member 4
CTD 12 Potassium channel tetramerisation domain containing NM_138444
12
KIAA0101 IAA0101 NMJM4736 IAA1 199 IAA1 199 NM_018689 IAA1 199 IAA 1 199 NM_018689 IAA1217 KIAA 1217 AK022045
KIAA1217 KIAA I 217 NM_019590
KIAA 1509 KIAA 1509 AB040942
KIAA1644 KIAA1644 protein AB05 143 I
KIAA1666 IAA 1666 protein BC035246
KIAA1913 IAA 1913 BC044246 IF18A inesin family member 18A NM_031217
KIF20A inesin family member 20A NM_005733 IF2C Kinesin family member 2C NM_006845 IF4A Kinesin family member 4A NMJM2310 LF2 Kruppel-like factor 2 (lung) NM_016270
KLK8 Kallikrein 8 (neuropsin/ovasin) NM_ 144505
KLRC 1 Killer cell lectin-like receptor subfamily C, member 1 NM_002259
KNTC2 Kinetochore associated 2 NM_00610I
KRT23 Keratin 23 (histone deacetylase inducible) NMJM5515
KRTAP1-5 Keratin associated protein 1-5 NM_031957
LAD1 Ladinin I NM_005558
LAMA2 Laminin, alpha 2 (merosin, congenital muscular NM_000426 dystrophy)
LEF1 Lymphoid enhancer-binding factor 1 NM_016269
LHX2 LIM homeobox 2 NM_004789
LIPE Lipase, hormone-sensitive NM_005357
LMNB 1 Lamin B l NM_005573
LOC I 26755 Hypothetical protein LOCI 26755 CR622769
LOCI 50166 Hypothetical protein LOCI 50166 AK056836
LOCI 50271 Hypothetical LOC388889 AK098753
LOC I 99964 Hypothetical protein LOCI 99964 NM 182532
LOC222171 Hypothetical protein LOC222171 NM 175887
LOC255480 Hypothetical protein LOC255480 AK091766
LOC284018 Hypothetical protein LOC284018 NM 181655
LOC285733 Hypothetical protein LOC285733 AK091900
LOC286254 Hypothetical protein LOC286254 AK092751
LOC5 1334 Mesenchymal stem cell protein DSC54 NM 016644
LOXL3 Lysyl oxidase-like 3 NM_032603
LOXL3 Lysyl oxidase-like 3 NM_032603
LPXN Leupaxin NM_00481 1
LRP8 Low density lipoprotein receptor-related protein 8, NM_033300 apolipoprotein e receptor
LYZ Lysozyme (renal amyloidosis) NM_000239
69
2613340-2 LZTS 1 Leucine zipper, putative tumor suppressor 1 NM_02I020
MAD2L 1 MAD2 mitotic arrest deficient-like 1 (yeast) NM_002358
MAFB V-maf musculoaponeurotic fibrosarcoma oncogene NM_005461 homolog B (avian)
MAGEA 1 Melanoma antigen, family A, 1 (directs expression of NM_004988 antigen MZ2-E)
MAL2 Mai, T-cell differentiation protein 2 NM_052886
MAOB Monoamine oxidase B NM_000898
MAP3 8 Mitogen-activated protein kinase kinase kinase 8 NM_005204
MARLIN 1 Multiple coiled-coil GAB ABR1 -binding protein NM_ 144720
MEST Mesoderm specific transcript homolog (mouse) NM_002402
MGAT3 Mannosyl (beta- 1 ,4-)-glycoprotein beta- 1 ,4-N- AK125361 acetylglucosaminyliransferase
MGC 13040 Hypothetical protein MGC 13040 NM_032930
MGC22265 Hypothetical protein MGC22265 BC048193
MGC2574 Hypothetical protein MGC2574 NM_024098
MGC2574 Hypothetical protein MGC2574 NM_024098
MGC33365 Hypothetical protein MGC33365 NM_173552
MLANA Melan-A NM_00551 1
MMP 12 Matrix metalloproteinase 12 (macrophage elastase) NM_002426
MSX 1 Msh homeo box homolog 1 (Drosophila) NM_002448
MT1 B Metaliothionein I B (functional) NM_005947
MT1 E Metallothionein I E (functional) NM_175617
MT1G Metaliothionein 1 G NM_005950
MT1 K Metallothionein I K NM 176870
MT1L Metallothionein 1L X97261
MT1X Metallothionein I X NM_005952
MT2A Metallothionein 2A NM_005953
MT2A Metallothionein 2A NM_005953
MTL5 Metallothionein-like 5, testis-specific (tesmin) NM_004923
MYCN V-myc myelocytomatosis viral related oncogene, NM_005378 neuroblastoma derived (avian)
MYO 10 Myosin X NM_012334
MYO 10 Myosin X NM_012334
MY05B Myosin VB AK025336
MY05C Myosin VC NM_018728
MYRIP Myosin VIIA and Rab interacting protein NM_015460
NAV2 Neuron navigator 2 NM 182964
NET1 Neuroepithelial cell transforming gene 1 NM_005863
NET02 Neuropilin (NRP) and tolloid (TLL)-like 2 NM_018092
NFE2 Nuclear factor (erythroid-derived 2), 45kDa NM_006163
NFIL3 Nuclear factor, interleukin 3 regulated NM 005384
NGEF Neuronal guanine nucleotide exchange factor NM_019850
NID2 Nidogen 2 (osteonidogen) NM_007361
NOSTRIN Nitric oxide synthase trafficker NM_052946
NOV Nephroblastoma overexpressed gene NM_0025 14
NR0B 1 Nuclear receptor subfamily 0, group B, member 1 NM_000475
NR0B2 Nuclear receptor subfamily 0, group B, member 2 NM_021969
NSE 1 NSE 1 NM_145175
NTN4 Netrin 4 NM_021229
NTS Neurotensin NM_006183
ODZ3 Odz, odd Oz/ten-m homolog 3 (Drosophila) AB040888
ODZ3 Odz, odd Oz/ten-m homolog 3 (Drosophila) AB040888
OIP5 Opa-interacting protein 5 NM_007280
OLFML2A Olfactomedin-like 2A NM_ 182487
OR7E140P Olfactory receptor, family 7, subfamily E, member 140 BC073935 pseudogene
70
2613340-2 OVOS2 Ovostatin 2 BC039 I 17
PAG Phosphoprotein associated with glycosphingolipid- NM_018440 enriched microdomains
PBEF1 Pre-B-cell colony enhancing factor 1 NM 005746
PBEF1 Pre-B-cell colony enhancing factor 1 NM 182790
PCANAP6 Prostate cancer associated protein 6 NM 033102
PCS 5 Proprotein convertase subtilisin/kexin type 5 NM 006200
PDGFA Platelet-derived growth factor alpha polypeptide NM 002607
PDGFC Platelet derived growth factor C NM 016205
PDGFD DNA-damage inducible protein 1 NM 025208
PHACTR 1 Phosphatase and actin regulator 1 NM_030948
PHLDA 1 Pleckstrin homology-like domain, family A, member 1 NM_007350
PHLDA 1 Pleckstrin homology-like domain, family A, member 1 NM 007350
PHLDB2 Pleckstrin homology-like domain, family B, member 2 NM_145753
PIK3R1 Phosphoinositide-3-kinase, regulatory subunit 1 (p85 NM_181523 alpha)
PIM1 Pim- 1 oncogene NM 002648
P D1 L2 Polycystic kidney disease 1 -like 2 NM 052892
P D2 Polycystic kidney disease 2 (autosomal dominant) NM_000297
PLAC8 Placenta-specific 8 NM 016619
PLAC8 Placenta-specific 8 NM 016619
PLD1 Phospholipase D l, phophatidylcholine-specific NM 002662
PL 2 Polo-like kinase 2 (Drosophila) NM 006622
PLP1 Proteolipid protein 1 (Pelizaeus-Merzbacher disease, M54927 spastic paraplegia 2, uncomplicated)
PMAIP1 Phorbol-12-myristate- 13-acetate-induced protein 1 NM 021 127
PPP1 R1 A Protein phosphatase 1 , regulatory (inhibitor) subunit 1 A NM_006741
PPP1 R3B Protein phosphatase 1 , regulatory (inhibitor) subunit 3B AK091994
PPP2R3A Protein phosphatase 2 (formerly 2A), regulatory subunit NM_002718
B", alpha
PRC1 Protein regulator of cytokinesis 1 NM_003981
PREX1 Phosphatidylinositol 3,4,5-trisphosphate-dependent NM_020820
RAC exchanger 1
PR CB 1 Protein kinase C, beta 1 NM_002738
PRKCB 1 Protein kinase C, beta 1 NM_002738
PROC Protein C (inactivator of coagulation factors Va and NM_OO0312
Villa)
PSCDBP Pleckstrin homology, Sec7 and coiled-coil domains, NM_004288 binding protein
PSD3 Pleckstrin and Sec7 domain containing 3 NM_015310
PSG 1 1 Pregnancy specific beta- 1 -glycoprotein 1 1 NM_002785
PSG3 Pregnancy specific beta- 1 -glycoprotein 3 NM 021016
PTGER4 Prostaglandin E receptor 4 (subtype EP4) NM_000958
PTGFR Prostaglandin F receptor (FP) NM 000959
PTTG1 Pituitary tumor-transforming 1 NM_004219
PTTG2 Pituitary tumor-transforming 2 NM 006607
RAB 1 1 FIP2 RAB 1 1 family interacting protein 2 (class I) NM 014904
RACGAP1 Rac GTPase activating protein 1 NM_013277
RAD52B RAD52 homolog B (S. cerevisiae) NM 145654
RAM 1 Receptor (calcitonin) activity modifying protein 1 NM 005855
RANBP9 RAN binding protein 9 NM 005493
RANBP9 RAN binding protein 9 NM 005493
RANBP9 RAN binding protein 9 NM 005493
RASD 1 RAS, dexamethasone-induced 1 NM 016084
REV3L REV3-like, catalytic subunit of DNA polymerase zeta NM_002912
(yeast)
RGS2 Regulator of G-protein signalling 2, 24kDa NM 002923
71
2613340-2 RI S3 Regulating synaptic membrane exocytosis 3 NM 014747
RIPK3 Receptor-interacting serine-threonine kinase 3 NM 006871
RIPK4 Receptor-interacting serine-threonine kinase 4 NM 020639
ROB03 Roundabout, axon guidance receptor, homolog 3 NM_022370
(Drosophila)
RPESP RPE-spondin NM 153225
RRM2 Ribonucleotide reductase M2 polypeptide NM 001034
RTN4R Reticulon 4 receptor NM_023004
SALL2 Sal-like 2 (Drosophila) NM 005407
SAMSN 1 SAM domain, SH3 domain and nuclear localisation NM_022136 signals, 1
SATB I Special AT-rich sequence binding protein 1 (binds to NM_002971 nuclear matrix/scaffold-associating DNA's)
SCIN Scinderin NM 033128
SECTM 1 Secreted and transmembrane 1 NM_003004
SEMA6A Sema domain, transmembrane domain (TM), and NM_020796 cytoplasmic domain, (semaphorin) 6A
SEPP1 Selenoprotein P, plasma, 1 NM_005410
SERPINA5 Serine (or cysteine) proteinase inhibitor, clade A NM_000624
(alpha- 1 antiproteinase, antitrypsin), member 5
SERPINA7 Serine (or cysteine) proteinase inhibitor, clade A NM_000354
(alpha- 1 antiproteinase, antitrypsin), member 7
SH2D 1A SH2 domain protein 1 A, Duncan's disease NM_002351
(lymphoproliferative syndrome)
SLC16A6 Solute carrier family 16 (monocarboxylic acid NM_004694 transporters), member 6
SLC1 A1 Solute carrier family 1 (neuronal/epithelia! high affinity NM_004170 glutamate transporter, system Xag), member 1
SLC20A I Solute carrier family 20 (phosphate transporter), NM_005415 member 1
SLC2A1 Solute carrier family 2 (facilitated glucose transporter), NM_006516 member 1
SLC39A8 Solute carrier family 39 (zinc transporter), member 8 NM_022154
SLC40A 1 Solute carrier family 40 (iron-regulated transporter), NM_014585 member 1
SLC7A5 Solute carrier family 7 (cationic amino acid transporter, NM_003486 y+ system), member 5
SLC9A9 Solute carrier family 9 (sodium/hydrogen exchanger), NM_ 173653 isoform 9
SLIT3 Slit homolog 3 (Drosophila) BC032027
SLPI Secretory leukocyte protease inhibitor NM_003064
(antileukoproteinase)
SM0C1 SPARC related modular calcium binding 1 NM_022137
SMOC2 SPARC related modular calcium binding 2 NM_022138
SNAI2 Snail homolog 2 (Drosophila) NM_003068
SNFT Jun dimerization protein p2 I SNFT NM_018664
SOCS 1 Suppressor of cytokine signaling 1 NM 003745
SORL1 Sortilin-related receptor, L(DLR class) A repeats- NM_003105 containing
SOX4 SRY (sex determining region Y)-box 4 AW946823
SOX4 SRY (sex determining region Y)-box 4 NM_0O31O7
SOX4 SRY (sex determining region Y)-box 4 NM 003107
SP5 Sp5 transcription factor NM_001003845
Spc25 inetochore protein Spc25 NM_020675
SPHK1 Sphingosine kinase 1 NM_021972
SPINT2 Serine protease inhibitor, Kunitz type, 2 NM_021 I02
SRC V-src sarcoma (Schmidl-Ruppin A-2) viral oncogene NM_005417 homolog (avian)
72
2613340-2 STAC SH3 and cysteine rich domain NM 003149
STC2 Stanniocalcin 2 NM 003714
STMN 1 Stathmin 1/oncoprotein 18 NM 203401
T3JAM TRAF3-interacting Jun N-terminal kinase (JN )- NM_025228 activating modulator
TCEAL7 Transcription elongation factor A (Sll)-like 7 NM 152278
TCF4 Transcription factor 4 AK021980
TIGD2 Tigger transposable element derived 2 NM 145715
TIMP3 Tissue inhibitor of metalloproteinase 3 (Sorsby fundus AA837799 dystrophy, pseudoinflammatory)
TK 1 Thymidine kinase 1 , soluble NM_003258
T 4SF1 Transmembrane 4 superfamily member 1 NM_014220
T PRSS4 Transmembrane protease, serine 4 NM 019894
TMSNB Thymosin, beta, identified in neuroblastoma cells NM_021992
TNC Tenascin C (hexabrachion) NM_002160
TncRNA Trophoblast-derived noncoding R A U60873
TNFAIP6 Tumor necrosis factor, alpha-induced protein 6 NM_0071 15
TNFRSF17 Tumor necrosis factor receptor superfamily, member 17 NM_001 192
TOP2A Topoisomerase (DNA) II alpha 170kDa NM_001067
TOPK T-LA cell-originated protein kinase NM_018492
TPD52 Tumor protein D52 NM_005079
TPM 1 Tropomyosin 1 (alpha) NM_000366
TPX2 TPX2, microtubule-associated protein homolog NM_0121 12
(Xenopus laevis) .
TRIB 1 Tribbles homolog 1 (Drosophila) NM 025195
TRIB2 Tribbles homolog 2 (Drosophila) NM_021643
TROAP Trophinin associated protein (tastin) NM_005480
TRPS 1 Trichorhinophalangeal syndrome I NM_0141 12
TT TTK protein kinase NM_003318
TXNIP Thioredoxin interacting protein NM_006472
TYRP1 Tyrosinase-related protein 1 NM_000550
UAP1 UDP-N-acteylglucosamine pyrophosphorylase 1 NM_0031 15
UBD Ubiquitin D NM_006398
UBE2C Ubiquitin-conjugating enzyme E2C NM_181803
UGT2B 1 1 UDP glycosyltransferase 2 family, polypeptide B 1 1 NM_001073
UST Uronyl-2-sulfotransferase NM_005715
UTS 2 Urotensin 2 NM_021995
UTS 2 Urotensin 2 NM_021995
VIL1 Villin 1 NM_007127
YPEL4 Yippee-like 4 (Drosophila) NM_ 145008
ZAP70 Zeia-chain (TCR) associated protein kinase 70kDa NM_001079
ZNF179 Zinc finger protein 179 NM_007148
ZNF503 Zinc finger protein 503 NM_032772
A 23 PI 5226
A 23 P170719
A_23_P43744
A_24_P290087
A_24_P686014
A_24_P927205
A_32_P182135
A_32_P205792
A_32_P225328
A_32_P232647
A_32_P55438
AF256215
Hypothetical gene supported by AK026189 AK022865
CDNA: FLJ22994 fis, clone KAT1 1918 AK026647
73
2613340-2
Figure imgf000076_0001
Figure imgf000077_0001
TABLE 5
Figure imgf000077_0002
75
2613340-2
Figure imgf000078_0001
CENPA Centromere protein A, 17kDa N _OOI809
76
2613340-2
Figure imgf000079_0001
EDN1 Endothelin 1 N _001955
77
2613340-2
Figure imgf000080_0001
78
2613340-2
Figure imgf000081_0001
79
2613340-2
Figure imgf000082_0001
80
2613340-2
Figure imgf000083_0001
81
2613340-2 PAPPA Pregnancy-associated plasma protein A, pappalysin 1 NM_002581
PAQR4 Progestin and adipoQ receptor family member IV NM_ 152341
PASD1 PAS domain containing 1 NM_ 173493
PBEF1 Pre-B-cell colony enhancing factor 1 NM_005746
PBEF1 Pre-B-cell colony enhancing factor 1 NM_005746
PBEF1 Pre-B-cell colony enhancing factor 1 NM_ 182790
PCS 5 Proprotein convertase subtilisin/kexin type 5 NM_006200
PDGFC Platelet derived growth factor C NM_016205
PEPP-2 PEPP subfamily gene 2 NM_032498
PHLDA 1 Pleckstrin homology-like domain, family A, member 1 NM_007350
Phosphoinositide-3-kinase, regulatory subunit 1 (p85
PI 3R1 NM_181523 alpha)
PIM 1 Pim- 1 oncogene NM_002648
PITX2 Paired-like homeodomain transcription factor 2 NM_ 153426
PLAC8 Placenta-specific 8 NMJM6619
PLAC8 Placenta-specific 8 NM_016619
PLD 1 Phospholipase D l , phophatidylcholine-specific NM_002662
PL 2 Polo-like kinase 2 (Drosophila) NM_006622
Procollagen-lysine, 2-oxoglutarate 5-dioxygenase (lysine
PL0D2 NM_ 182943 hydroxylase) 2
Proteolipid protein 1 (Pelizaeus-Merzbacher disease,
PLP1 M54927 spastic paraplegia 2, uncomplicated)
PMAIP 1 Phorbol-12-myristate-13-acetate-induced protein 1 NM_021 127
P0N3 Paraoxonase 3 NM_000940
POSTN Periostin, osteoblast specific factor NM_006475
PPP1 R1 A Protein phosphatase 1 , regulatory (inhibitor) subunit 1A NM_006741
PPP1 R3B Protein phosphatase 1 , regulatory (inhibitor) subunit 3B AK091994
PRC1 Protein regulator of cytokinesis 1 NM_003981
Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC
PREX 1 NM_020820 exchanger 1
PSD3 Pleckstrin and Sec7 domain containing 3 NM_015310
PSD3 Pleckstrin and Sec7 domain containing 3 NM 015310
PSG 1 Pregnancy specific beta- 1 -glycoprotein 1 NM_006905
PSG3 Pregnancy specific beta- 1 -glycoprotein 3 NM_021016
PTGFR Prostaglandin F receptor (FP) NM_000959
PTGIR Prostaglandin 12 (prostacyclin) receptor (IP) NM_000960
PTTG 1 Pituitary tumor-transforming 1 NM_004219
PTTG2 Pituitary tumor-transforming 2 NM_006607
RACGAP1 Rac GTPase activating protein 1 NM_013277
RAMP1 Receptor (calcitonin) activity modifying protein 1 NM_005855
RANBP9 RAN binding protein 9 NMJJ05493
RANBP9 RAN binding protein 9 NM_005493
RASD 1 RAS, dexamethasone-induced 1 NM_016084
RAS guanyl releasing protein 1 (calcium and DAG-
RASGRP 1 NM_005739 regulated)
RGS2 Regulator of G-protein signalling 2, 24kDa NM_002923
RIPK3 Receptor-interacting serine-threonine kinase 3 NM_006871
RTN4R Reticulon 4 receptor NM_0230O4
S 100B S I 00 calcium binding protein, beta (neural) NM_006272
82
2613340-2
Figure imgf000085_0001
83
2613340-2
Figure imgf000086_0001
84
2613340-2
Figure imgf000087_0001
Figure imgf000088_0001
This invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having," "containing," "involving," and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
Each of the foregoing patents, patent applications and references is hereby incorporated by reference, particularly for the teaching referenced herein.
****
Having thus described several aspects of at least one embodiment of this invention, it is to be appreciated various alterations, modifications, and improvements will readily occur to
86
2613340:2 those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description and drawings are by way of example only.
87
2613340-2 Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUMl_OUGO_A_24_P745883 A_24_P745883 0.032464275
AGI_HUMl_OUGO_A_24_P243396 NM_001008657 0.039492348
AGI_HUM1_OUGO_A_24_P53080 ETFA Electron-transfer-flavoprotein, alpha polypeptide (glutaric aciduria II) NM_000126 2108 0.039492348
AGI_HUM1_OUGO_A_23_P117298 F7 Coagulation factor VII (serum prothrombin conversion accelerator) NM_000131 2155 0.060597251
AGI_HUMl_OUGO_A_23_P14124 ASL11A RAS-like, family 11, member A NM_206827 387496 0.060597251
AGI_HUM1_OLIGO_A_23_P156708 TNXB Tenascin XB N _019105 7148 0.060597251
AGI_HU 1_OLIGO_A_23_P205177 F10 Coagulation factor X N _000504 2159 0.060597251
AGI_HUM1_OUGO_A_23_P345650 IAA1280 IAA1280 protein NM_015691 55841 0.060597251
AGI_H U M 1_0 U GO_A_23_P5281 LYL1 Lymphoblastic leukemia derived sequence 1 NM_005583 4066 0.060597251
AGI_HUMl_OLIGO_A_24_P169843 A_24_P169843 0.060597251
AGI_HUM1_OUGO_A_24_P180383 NIPBL Nipped-B homolog (Drosophila) NM_015384 25836 0.060597251
AGI_HUM1_OUGO_A_24_P185604 NDRG3 NDRG family member 3 NM_032013 57446 0.060597251
AGI_HUMl_OUGO_A_24_P29966 TRIM32 Tripartite motif-containing 32 NM_012210 22954 0.060597251
AGI_HUMl_OLIGO_A_24_P727884 G2 G2 protein U10991 25758 0.060597251
AGI_HUM1_OUGO_A_24_P924040 SSFA2 Sperm specific antigen 2 NM_006751 6744 0.060597251
AGI_HUMl_OLIGO_A_23_P165783 MLPH Melanophilin NM_024101 79083 0.068421106
AGI_HUMl_OLIGO_A_23_P162866 HSPCA Heat shock 90kDa protein 1, alpha NM_005348 3320 0.070083415
AGI_HUMl_OLIGO_A_23_P44363 CASKIN2 CASK interacting protein 2 NM_020753 57513 0.070083415
AGI_HUMl_OUGO_A_23_P45324 TME 35 Transmembrane protein 35 NM_021637 59353 0.070083415
AGI_HUM1_OLIGO_A_23_P130418 NDUFV2 NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa NM_021074 4729 0.075584295
AGI_HU 1_OUGO_A_23_P203115 TMEM25 Transmembrane protein 25 NM_032780 84866 0.075584295
AGI_HUM1_OLIGO_A_23_P502363 EYA1 Eyes absent homolog 1 (Drosophila) NM_000503 2138 0.075584295
AGI_H U M 1_0 LI GO_A_23_P52227 GDF10 Growth differentiation factor 10 NM_004962 2662 0.075584295
AGI_HUM1_OUGO_A_23_P94103 MGC45780 Hypothetical protein MGC45780 NM_173833 286133 0.075584295
AGI_HUM1_OUGO_A_24_P607904 ITGA9 Integrin, alpha 9 AK026826 3680 0.075584295
AGI_HUM1_OLIGO_A_23_P106532 D4ST1 Dermatan 4 sulfotransferase 1 NM_130468 113189 0.083158024
AGI_HUM1_OUGO_A_23_P111860 FU 10324 Hypothetical protein FU 10324 NM_018059 55698 0.083158024
AGI_HUM1_OUGO_A_23_P11664 SFRS11 Splicing factor, arginine/serine-rich 11 NM_004768 9295 0.083158024
AGI_HUM1_OLIGO_A_23_P121533 SPON2 Spondin 2, extracellular matrix protein NM_012445 10417 0.083158024 00
00
AGI_HU l_OUGO_A_23_P133694 SLC29A1 Solute carrier family 29 (nucleoside transporters), member 1 NM_004955 2030 0.083158024
AGI_HU 1_OUGO_A_23_P153640 ANKRD27 Ankyrin repeat domain 27 (VPS9 domain) NM_032139 84079 0.083158024
Mannan-binding lectin serine protease 1 (C4/C2 activating component of Ra-
AGI_HUMl_OUGO_A_23_P212263 MASP1 reactive factor) NM_139125 5648 0.083158024
AGI_HUMl_OLIGO_A_23_P212339 FYCOl FYVE and coiled-coil domain containing 1 NM_024513 79443 0.083158024
AGI_HUMl_OUGO_A_23_P21324 TWIST2 Twist homolog 2 (Drosophila) NM_057179 117581 0.083158024
AGI_HUMl_OLIGO_A_23_P253982 H0XA4 Homeo box A4 NM_002141 3201 0.083158024
AGI_HUM1_OLIGO_A_23_P28507 GC52110 Hypothetical protein MGC52110 NM_012214 493753 0.083158024
Procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), alpha
AGI_HUM1_OLIGO_A_23_P30363 P4HA2 polypeptide II N _004199 8974 0.083158024
AGI_HU l_OUGO_A_23_P345692 IL17D Interleukin 17D NM_138284 53342 0.083158024
AGI_HU l_OLIGO_A_23_P3562 FU13291 Hypothetical protein FU13291 NM_032178 84138 0.083158024
AGI_HUM1_OLIGO_A_23_P40072 MT1F2 Mitochondrial translational initiation factor 2 NM_001005369 4528 0.083158024
AGI_HUMl_OUGO_A_23_P41976 LOC133957 Similar to RIKEN cDNA 0610011N22 NM_145265 133957 0.083158024
AGI_HUM1_OUGO_A_23_P422851 CABLES1 Cdk5 and Abl enzyme substrate 1 NM_138375 91768 0.083158024
AGI_HUM1_OLIGO_A_23_P430181 2BTB3 Zinc finger and BTB domain containing 3 NM_024784 79842 0.083158024
AGI_HU l_OUGO_A_23_P432598 Shax3 Snf7 homologue associated with Alix 3 NM_152284 92421 0.083158024
AGI_HU 1_OUGO_A_23_P433016 FBLN1 Fibulin 1 NM_001996 2192 0.083158024
AGI_HUM1_OUGO_A_23_P500410 ATP6V1G2 ATPase, H+ transporting, lysosomal 13kDa, VI subunit G isoform 2 NM_130463 534 0.083158024
AGI_HUMl_OLIGO_A_23_P56578 IT Vitrin NM_053276 5212 0.083158024
AGI_HUMl_OUGO_A_23_P74229 MGC4796 Ser/Thr-like kinase NM_032017 83931 0.083158024
AGI_HUMl_OUGO_A_23_P77568 EIF3S8 Eukaryotic translation initiation factor 3, subunit 8, HOkDa NM_003752 8663 0.083158024
AGI_HUM1_OLIGO_A_23_P8240 FAM50B Family with sequence similarity 50, member B NM_012135 26240 0.083158024
AGI_HUMl_OLIGO_A_23_P87839 SFRS2IP Splicing factor, arginine/serine-rich 2, interacting protein NM_004719 9169 0.083158024
AGI_HUM1_OLIGO_A_24_P137501 SFRP2 Secreted frizzled-related protein 2 NM_003013 6423 0.083158024
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
o
AGI_HUMl_OUGO_A_24_P184385 LOC220074 Hypothetical 55.1 kDa protein F09G8.5 in chromosome III NM_145309 220074 0.083158024
O
r~ AGI_HUMl_OUGO_A_24_P184388 LOC220074 Hypothetical 55.1 kDa protein F09G8.5 in chromosome III NM_145309 220074 0.083158024
AGI_HUMl_OUGO_A_24_P365954 THAP11 THAP domain containing 11 NM_020457 57215 0.083158024 o AGI_HUM1_OUGO_A_24_P406514 UBE2V2 Ubiquitin-conjugating enzyme E2 variant 2 NM_003350 7336 0.083158024
AGI_HUMl_OUGO_A_24_P48862 SNAP29 Synaptosomal-associated protein, 29kDa NM_004782 9342 0.083158024
AGI_HUM1_OUGO_A_24_P598406 RBAK RB-associated KRAB repressor BC068459 57786 0.083158024
AGI_HU 1_OUGO_A_24_P71700 KIAA1190 Hypothetical protein KIAA1190 NM_145166 92999 0.083158024
AGI_HUM1_OUGO_A_24_P7470 A_24_P7470 0.083158024
AGI_HUM l_OUGO_A_24_P916916 CYP3A5 Cytochrome P450, family 3, subfamily A, polypeptide 5 AF355801 1577 0.083158024
AGI_HUM1_OLIGO_A_24_P98109 SNX10 Sorting nexin 10 NM_013322 29887 0.083158024
AGI_HUM1_OUGO_A_32_P120084 HSPC128 HSPC128 protein NM_014167 29080 0.083158024
AGI_HUM1_OUGO_A_32_P35220 CBWD1 COBW domain containing 1 NM_172003 55871 0.083158024
AGI_HUMl_OLIGO_A_32_P58163 C15orf29 Chromosome 15 open reading frame 29 NM_024713 79768 0.083158024
AGI_HUM1_OUGO_A_23_P100022 SV2B Synaptic vesicle glycoprotein 2B NM_014848 9899 0.083256971
AGI_HUM1_0UG0_A_23_P114423 RGN Regucalcin (senescence marker protein-30) NM_004683 9104 0.083256971
AGl_HUMl_OUGO_A_23_P119857 NM_001008237 0.083256971
AGI_HUMl_OUGO_A_23_P143981 FBLN2 Fibulin 2 NM_001004019 2199 0.083256971
AGI_HUMl_OUGO_A_23_P151895 CI LP Cartilage intermediate layer protein, nucleotide pyrophosphohydrolase NM_003613 8483 0.083256971
AGI_HUMl_OUGO_A_23_P155835 CYP2U1 Cytochrome P450, family 2, subfamily U, polypeptide 1 NM_183075 113612 0.083256971
AGI_HUMl_OUGO_A_23_P157736 C9orf67 Chromosome 9 open reading frame 67 NM_032728 84814 0.083256971
AGI_HU 1_OUGO_A_23_P170649 RPESP RPE-spondin NM_153225 157869 0.083256971
AGI_HUM1_OUGO_A_23_P200015 AK5 Adenylate kinase 5 · NM_174858 26289 0.083256971
AGI_HUM1_OUGO_A_23_P204286 MGP Matrix Gla protein NM_000900 4256 0.083256971
AGI_HUM1_OLIGO_A_23_P209987 P0LR1B Polymerase (RNA) I polypeptide B, 128kDa NM_019014 84172 0.083256971
AGI_HUMl_OLIGO_A_23_P214281 C6orf33 Chromosome 6 open reading frame 33 NM_133367 85315 0.083256971
AGI_HU l_OUGO_A_23_P22647 TME 28 Transmembrane protein 28 NM_015686 27112 0.083256971
AGI_HUM1_OUGO_A_23_P27810 ZNF607 Zinc finger protein 607 NM_032689 84775 0.083256971
AGI_HU l_OUGO_A_23_P367899 EPOR Erythropoietin receptor NM_000121 2057 0.083256971
AGI_HUM1_OUGO_A_23_P391906 KIAA1913 KIAA1913 BC044246 114801 0.083256971 CD
AGI_HUM1_OLIGO_A_23_P398044 MGC20255 Hypothetical protein MGC20255 NM_052848 90324 0.083256971 CO
AGI_HUM1_OUGO_A_23_P415006 RAB11FIP5 RAB11 family interacting protein 5 (class I) NM_015470 26056 0.083256971
AGI_HUM1_OUGO_A_23_P421401 PDGFRB Platelet-derived growth factor receptor, beta polypeptide NM_002609 5159 0.083256971
AGI_HUMl_OUGO_A_23_P69738 RASL11B RAS-like, family 11, member B NM_023940 65997 0.083256971
AGI_HUMl_OUGO_A^.23_P76136 Similar to Peptidylprolyl isomerase A, isoform 1 AY358804 390299 0.083256971
AGI_HUMl_OLIGO_A_23_P76749 NM_020692 0.083256971
AGI_HUMl_OUGO_A_23_P83579 ARNT2 Aryl-hydrocarbon receptor nuclear translocator 2 NM_014862 9915 0.083256971
AGI_HUMl_OLIGO_A_23_P99226 SIRT4 Sirtuin (silent mating type information regulation 2 homolog) 4 (S. cerevisiae) NM_012240 23409 0.083256971
AGI_HUMl_OUGO_A_24_P156886 D FZP564B1023 Hypothetical protein DKFZp564B1023 NM_031306 83479 0.083256971
AGI_HUMl_OUGO_A_24_P217330 FU14566 Hypothetical protein FU 14566 NM_032806 84892 0.083256971
AGI_HU 1_OUGO_A_24_P217489 GLRB Glycine receptor, beta NM_000824 2743 0.083256971
AGI_HUMl_OLIGO_A_24_P245298 TNFSF13 Tumor necrosis factor (ligand) superfamily, member 12 NM_003809 8741 0.083256971
AGI_HUMl_OUGO_A_24_P414719 L0C221442 Hypothetical protein LOC221442 AK002098 221442 0.083256971
AGI_HUMl_OLIGO_A_24_P475556 LOC 146346 Hypothetical protein LOC146346 AK057359 146346 0.083256971
*0 AGI_HUM1_OLIGO_A_24_P720185 BC092421 0.083256971
90 Similar to Gamma-glutamyltranspeptidase 1 precursor (Gamma- 90 AGI_HUM l_OUGO_A_24_P83848 glutamyltransferase 1) (CD224 antigen) M30474 440796 0.083256971
AGI_HUMl_OUGO_A_32_P113887 THC2446900 0.083256971
AGI_HUMl_OUGO_A_32_P42574 FU14525 Hypothetical protein FU14525 NM_032800 84886 0.083256971
O AGI_HUMl_OUGO_A_32_P5251 RARA Retinoic acid receptor, alpha NM_000964 5914 0.083256971
AGI_HUM1_OUGO_A_32_P6408 DKFZp547K0S4 Hypothetical protein D FZp547K054 AL390175 56974 0.083256971 o AGI_HU 1_OUGO_A_32_P64096 NM_001012981 0.083256971
AGI_HUMl_OUGO_A_23_P19322 C6orf64 Chromosome 6 open reading frame 64 NM_018322 55776 0.083597114
AGI_HUM1_OUGO_A_23_P201672 IAA0859 KIAA0859 NM_015935 51603 0.083597114
AGI_HUM1_OUGO_A_23_P322704 C14orf24 Chromosome 14 open reading frame 24 NM_173607 283635 0.083597114
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_OLIGO_A_23_P403445 CGREF1 Cell growth regulator with EF hand domain 1 NM_006569 10669 0.083597114
AGI_HUMl_OLIGO_A_23_P82929 · NOV Nephroblastoma overexpressed gene NM_002514 4856 0.083597114
AGI_HUM1_OUGO_A_23_P89410 BECN1 Beclin 1 (coiled-coil, myosin-like BCL2 interacting protein) NM_003766 8678 0.083597114
AGI_HUMl_OUGO_A_24_P943613 TBC1D1 TBC1 (tre-2/USP6, BUB2, cdd6) domain family, member 1 NM_015173 23216 0.083597114
AGI_HU 1_OLIGO_A_32_P84009 CKLFSF4 Chemokine-like factor super family 4 NM_178818 146223 0.083597114
AGI_HUM1_OUGO_A_24_P109652 ΚΙΑΑ20Ό2 KIAA2002 protein AB082533 79834 0.083793896
AGI_HUM1_OUGO_A_23_P50167 SLC39A6 Solute carrier family 39 (zinc transporter), member 6 NM_012319 25800 0.083837055
AGI_HUMl_OUGO_A_23_P158231 APBA2 Amyloid beta (A4) precursor protein-binding, family A, member 2 (Xll-like) NM_005503 321 0.085898602
AGI_HUM1_OUGO_A_23_P201338 Cab45 Calcium binding protein Cab45 precursor NM_016176 51150 0.085898602
AGI_HUM1_OUGO_A_23_P209499 PAX3 Paired box gene 3 (Waardenburg syndrome 1) NM_181458 5077 0.085898602
AGI_HU l_OUGO_A_23_P26534 HCFC1R1 Host cell factor CI regulator 1 (XPOl dependant) NM_017885 54985 0.085898602
AGI_HUM1_OLIGO_A_24_P931944 CDNA FU25106 fis, clone CBR01467 AK128814 0.086294408
AGl_HUMl_OUGO_A_23_P153489 SCGF Stem cell growth factor; lymphocyte secreted C-type lectin NM_002975 6320 0.086334725
AGI_HUM1_OUGO_A_23_P103601 MAN1C1 Mannosidase, alpha, class 1C, member l NM.020379 57134 0.08767326
AGI_HUMl_OLIGO_A_23_P168951 ZHX2 Zinc fingers and homeoboxes 2 NM_014943 22882 0.08767326
AG1_HUM1_0UG0_A_24_P316364 DKFZP566E144 Small fragment nuclease NM_015523 25996 0.08767326
AGI_HUM1_OUGO_A_32_P170925 ENST0000036020: 0.08767326
AG1_HUM1_0UG0_A_23_P112311 TRIM32 Tripartite motif-containing 32 NM_012210 22954 0.087758013
AGI_HUM1_OLIGO_A_23_P201002 FU 10597 Hypothetical protein FU 10597 NM_018150 55182 0.087758013
Serine (or cysteine) proteinase inhibitor, clade A (alpha-1 antiproteinase,
AGI_HUM1_OUGO_A_23_P205355 SERPINAS antitrypsin), member 5 NM_000624 5104 0.087758013
AGI_HUM1_OLIGO_A_23_P26890 MP28 Matrix metalloproteinase 28 NM_024302 79148 0.087758013
AGI_HUM1_OUGO_A_23_P390596 PS H1 Protein serine kinase HI NM_006742 5681 0.087758013
AGI_HUMl_OUGO_A_24_P375132 A_24_P375132 0.087758013
AGI_HUMl_OLIGO_A_24_P382489 SLC27A1 Solute carrier family 27 (fatty acid transporter), member 1 NM_198580 •376497 0.087758013
AGI_HU l_OUGO_A_24_P89872 ZNF189 Zinc finger protein 189 NM_197977 7743 0.087758013
AGI_HUM1_OUGO_A_23_P12363 ROR1 Receptor tyrosine kinase-like orphan receptor 1 NM_005012 4919 0.088567004
AGI_HU l_OLIGO_A_23_P131887 U35612 0.088567004
AGI_HUM l_OUGO_A_23_P149496 FU10307 Hypothetical protein FU10307 NM_018053 55113 0.088567004
AGI_HUMl_OUGO_A_23_P162746 CRYL1 Crystallin, lambda 1 NM_015974 51084 0.088567004
AGI_HUMl_OLIGO_A_23_P165927 STMN3 Stathmin-like 3 NM_015894 50861 0.088567004
AGI_HUM l_OLIGO_A_23_P211680 MLC1 Megalencephalic leukoencephalopathy with subcortical cysts 1 NM_015166 23209 0.088567004
AGI_HUM1_OUGO_A_23_P214908 FTHFSDC1 Formyltetrahydrofolate synthetase domain containing 1 AY374131 25902 0.088567004
AGI_HUMl_OUGO_A_23_P2216 HRB2 HIV-1 rev binding protein 2 NM_007043 11103 0.088567004
AGI_HUM1_OLIGO_A_23_P311640 HRBL HIV-1 Rev binding protein-like NM_006076 3268 0.088567004
AGI_HUMl_OUGO_A_23_P31399 PON2 Paraoxonase 2 NM_000305 5445 0.088567004
AGI_HU 1_0U GO_A_23_P357185 CHDH Choline dehydrogenase NM_018397 55349 0.088567004
AGI_HU l_OLIGO_A_23_P377819 SFRS5 Splicing factor, arginine/serine-rich 5 NM_006925 6430 0.088567004
AGI_HUM1_OLIGO_A_23_P500892 TUB Tubby homolog (mouse) NM_003320 7275 0.088567004
AGI_HU 1_OUGO_A_23_P501134 UG3 Ligase III, DNA, ATP-dependent NM_002311 3980 0.088567004
AGI_HUM1_OLIGO_A_23_P52017 ASPM Asp (abnormal spindle)-like, microcephaly associated (Drosophila) NM_018136 259266 0.088567004
AGI_HUM1_OLIGO_A_23_P54041 THTPA Thiamine triphosphatase NM_024328 79178 0.088567004
AGI_HUMl_OLIGO_A_23_P94889 CGI-90 CGI-90 protein BX640636 51115 0.088567004
AGI_HUM1_OUGO_A_24_P230877 CDNA FU33330 fis, clone BRACE2000441 BC009463 0.088567004
AGI_HUMl_OUGO_A_24_P322635 EL 02 Engulfment and cell motility 2 (ced-12 homolog, C. elegans) NM_182764 63916 0.088567004
AGI_HUM1_OUGO_A_24_P336728 NM_014873 0.088567004
AGI_HUM1_OUGO_A_24_P370702 GBP3 Guanylate binding protein 3 NM_018284 2635 0.088567004
AGI_HUM1_OLIGO_A_24_P399065 SDOS Hypothetical protein MGC11275 NM_032349 84309 0.088567004
AGI_HUMl_OLIGO_A_24_P413988 TGOLN2 Trans-golgi network protein 2 NM_006464 10618 0.088567004
AGI_HUM1_OUGO_A_24_P683905 Hypothetical gene supported by AK001829 AK001829 440498 0.088567004
AGI_HUM1_OLIGO_A_24_P73290 ATP2A2 ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 NM_001681 488 0.088567004
AGI_HUMl_OUGO_A_24_P76313 FAM43B Family with sequence similarity 43, member B NM_207334 163933 0.088567004
AGI_HUM1_OUGO_A_24_P867201 Homo sapiens, clone IMAGE:5277945, mRNA CR613944 0.088567004
AGI_HUMl_OLIGO_A_24_P94722 TMEM34 Transmembrane protein 34 NM_018241 55751 0.088567004
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_OLIGO_A_32_P108738 DKFZp761B107 Hypothetical protein DKFZp761B107 AK023472 91050 0.088567004
AGI_HUMl_OUGO_A_32_P11372 FU30435 Hypothetical protein FU30435 NM_174950 387628 0.088567004
AGI_HUMl_OLIGO_A_32_P149967 Transcribed locus BX105952 0.088567004
AGI_HUMl_OUGO_A_32_P196142 THC2400010 0.088567004
AGI_HUMl_OLIGO_A_23_P165778 MLPH Melanophilin NM_024101 79083 0.088872647
AGI_HUM1_OUGO_A_23_P107552 KIAA1012 KIAA1012 NM_014939 22878 0.089684374
AGI_HUM1_OUGO_A_23_P203389 MGC13379 HSPC244 N _016499 51259 0.089684374
AGI_HUMl_OLIGO_A_23_P416965 DKFZP564J102 D FZP564J102 protein NM_015398 25854 0.089684374
AGI_HUMl_OUGO_A_24_P225679 IRS1 Insulin receptor substrate 1 NM_005544 3667 0.089684374
AGI_HUM1_OLIGO_A_24_P944054 CXCL12 Chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1) AK090482 6387 0.089684374
AGI_HUMl_OUGO_A_23_P11764 EIF2C1 Eukaryotic translation initiation factor 2C, 1 NM_012199 26523 0.09025495
AGI_HU l_OUGO_A_23_P138725 MARVELD1 MARVEL domain containing 1 NM_031484 83742 0.09025495
AGI_HU l_OLIGO_A_23_P139965 NM_001010897 0.09025495
AGI_HUM1_OLIGO_A_24_P133085 MDS025 Hypothetical protein MDS025 NM_021825 60492 0.09025495
AGI_HUMl_OUGO_A_24_P56467 GMPR2 Guanosine monophosphate reductase 2 NM_001002000 51292 0.09025495
AGI_HUMl_OLIGO_A_32_P222362 DRG1 Developmentally regulated GTP binding protein 1 A 127132 4733 0.09025495
AGI_HUM1_OUGO_A_23_P102462 FU37440 Hypothetical protein FU37440 NM_153214 129804 0.090484176
AGI_HUM1_OUGO_A_23_P103398 PSEN2 Presenilin 2 (Alzheimer disease 4) NM_000447 5664 0.090484176
AGI_HUM l_OLIGO_A_23_P 112673 FU10036 Zwilch NM_017975 55055 0.090484176
AGI_H U M l_OLI GO_A_23_P 117190 DNAJD1 DnaJ (Hsp40) homolog, subfamily D, member 1 NM_013238 29103 0.090484176
AGI_HUM l_OUGO_A_23_Pl 20472 TFAP2C Transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma) NM_003222 7022 0.090484176
AGI_HU 1_OUGO_A_23_P120942 G22P1 Thyroid autoantigen 70kDa (Ku antigen) NM_001469 2547 0.090484176
AGI_HU l_OUGO_A_23_P121686 SCYE1 Small inducible cytokine subfamily E, member 1 (endothelial monocyte-activating) NM_004757 9255 0.090484176
AGI_HUMl_OUGO_A_23_P128613 KDELC1 KDEL (Lys-Asp-Glu-Leu) containing 1 NM_024089 79070 0.090484176
AGI_HUM1_OUGO_A_23_P133506 DOK3 Docking protein 3 NM_024872 79930 0.090484176
AGI_HUMl_OUGO_A_23_P139455 FU14451 Hypothetical protein FU14451 NM_032786 84872 0.090484176
AGI_HU 1_OUGO_A_23_P139509 PTX1 PTX1 protein NM_016570 51290 0.090484176
AGI_HUM1_OUGO_A_23_P147025 RAB33A RAB33A, member RAS oncogene family NM_004794 9363 0.090484176
AGI_HUMl_OUGO_A_23_P147495 BCORL1 BCL6 co-repressor-like 1 NM_021946 63035 0.090484176
AGI_HUMl_OLIGO_A_23_P147874 GC3234 Hypothetical protein MGC3234 NM_023947 66005 0.090484176
AGI_HUM1_OUGO_A_23_P149042 PYCR2 Pyrroline-5-carboxylate reductase family, member 2 NM_013328 29920 0.090484176
AGI_HUM1_OLIGO_A_23_P150267 BBS1 Bardet-Biedl syndrome 1 NM_024649 582 0.090484176
AGI_HUMl_OUGO_A_23_P151529 C14orfl32 Chromosome 14 open reading frame 132 NM_020215 56967 0.090484176
AGI_HU l_OUGO_A_23_P 154349 HIBCH 3-hydroxyisobutyryl-Coenzyme A hydrolase NM_014362 26275 0.090484176
AGI_HUMl_OUGO_A_23_P155765 HMGB2 High-mobility group box 2 NM_002129 3148 0.090484176
AGI_HUMl_OUGO_A_23_P156667 PPP1R10 Protein phosphatase 1, regulatory subunit 10 NM_002714 5514 0.090484176
AGI_HUMl_OUGO_A_23_P156842 EEF1E1 Eukaryotic translation elongation factor 1 epsilon 1 NM_004280 9521 0.090484176
AGI_HUMl_OLIGO_A_23_P162142 TS Likely ortholog of chicken tsukushi NM_015516 25987 0.090484176
AGl_HUMl_OUGO_A_23_P162846 LA P1 Lysosomal-associated membrane protein 1 NM_005561 3916 0.090484176
AGI_HUMl_OUGO_A_23_P165952 ACTR5 ARP5 actin-related protein 5 homolog (yeast) NM_024855 79913 0.090484176
AGI_HUM1_OUGO_A_23_P166087 RASSF2 Ras association (RalGDS/AF-6) domain family 2 NM_014737 9770 0.090484176
AGI_HUMl_OUGO_A_23_P166566 FU 12057 Hypothetical protein FU120S7 NM_024768 79825 0.090484176
AGI_HUMl_OUGO_A_23_P168479 RALA V-ral simian leukemia viral oncogene homolog A (ras related) NM_005402 5898 0.090484176
AGI_HUMl_OUGO_A_23_P169117 RRAGA Ras-related GTP binding A NM_006570 10670 0.090484176
AGI_HUM1_OUGO_A_23_P18082 FU14566 Hypothetical protein FU 14566 NM_032806 84892 0.090484176
Potassium large conductance calcium-activated channel, subfamily M, beta
AGI_HUMl_OUGO_A_23_P19142 KCNMB1 member 1 NM_004137 3779 0.090484176
AGI_HUM1_OLIGO_A_23_P204511 FU20489 Hypothetical protein FU20489 NM_017842 55652 0.090484176
AGI_HU 1_OUGO_A_23_P205370 ASB2 Ankyrin repeat and SOCS box-containing 2 NM_016150 51676 0.090484176
AGI_HUM1_OUGO_A_23_P205435 NOVA1 Neuro-oncological ventral antigen 1 NM_002515 4857 0.090484176
AGI_HUM1_OUGO_A_23_P206788 AP1G1 Adaptor-related protein complex 1, gamma 1 subunit NM_001128 164 0.090484176
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
Thyroid hormone receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene
AGI_HUM1_OUGO_A_23_P207742 THRA homolog, avian) NM_003250 7067 0.090484176
AGI_HUM1_OUGO_A_23_P207999 P AIP1 Phorbol-12-myristate-13-acetate-lnduced protein 1 NM_021127 5366 0.090484176
AGI_H UM l_OLIGO_A_23_P211631 FBLN1 Fibulin 1 NM_006486 2192 0.090484176
AGI_HU l_OUGO_A_23_P212213 THU PD3 THUMP domain containing 3 NM_015453 25917 0.090484176
AGI_HUMl_OLIGO_A_23_P24135 TACR2 Tachykinin receptor 2 NM_001057 6865 0.090484176
AGI_HUM1_OLIGO_A_23_P250102 ENST0000029598' 0.090484176
AGI_HUM1_OUGO_A_23_P25060 FU 13769 Hypothetical protein FU13769 AK023831 80079 0.090484176
AGI_HUM 1_OLIGO_A_23_P250930 CRBN Cereblon NM_016302 51185 0.090484176
AGI_HUM 1_OUGO_A_23_P254081 LIAS Lipoic acid synthetase NM_006859 11019 0.090484176
AGI_HUM 1_OUGO_A_23_P254702 OEK DEK oncogene (DNA binding) NM_003472 7913 0.090484176
AGI_HUMl_OUGO_A_23_P26314 ZNF319 Zinc finger protein 319 NM_020807 57567 0.090484176
AGI_HUM1_OLIGO_A_23_P27035 DKF2P564 1964 DKFZP564K1964 protein NM_015544 26022 0.090484176
AGI_HUMl_OUGO_A_23_P27584 NM_001020818 0.090484176
CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) small
AGI_HUM l_OUGO_A_23_P28263 CTDSPl phosphatase 1 NM_021198 58190 0.090484176
AGI_HUM 1_OLIGO_A_23_P30020 PLA2G12A Phospholipase A2, group XIIA NM_030821 81579 0.090484176
AGI_HUM1_OLIGO_A_23_P303763 ZNF79 Zinc finger protein 79 (pT7) N _007135 7633 0.090484176
AGI_HUM1_OLIGO_A_23_P303833 SCN4B Sodium channel, voltage-gated, type IV, beta NM_174934 6330 0.090484176
AGI_HUM l_OUGO_A_23_P310956 COL6A2 Collagen, type VI, alpha 2 NM_058175 1292 0.090484176
AGI_HUMl_OUGO_A_23_P327426 MGC3794 Putative MAPK activating protein NM_152902 261726 0.090484176
AGI_HUM1_OUGO_A_23_P331908 PRDM11 PR domain containing 11 AK097878 56981 0.090484176
AGI_HUM1_OLIGO_A_23_P34402 NCSTN Nicastrin NM_015331 23385 0.090484176
AGI_HUM l_OLrGO_A_23_P345674 ZNF71 Zinc finger protein 71 (Cos26) NM_021216 58491 0.090484176
AGI_HU 1_OUGO_A_23_P350824 DPYSL2 Dihydropyrimidinase-like 2 NM_001386 1808 0.090484176
AGI_HUM1_OLIGO_A_23_P352950 PNMA5 Paraneoplastic antigen like 5 NM_052926 114824 0.090484176
AGI_HUM l_OUGO_A_23_P35617 PLCE 1 Phospholipase C, epsilon l NM_016341 51196 0.090484176
AGI_HUM l_OUGO_A_23_P357936 AST 2 Astrotactin 2 NM_014010 23245 0.090484176
AGI_HUM 1_OUGO_A_23_P360964 MGC15476 Thymus expressed gene 3-like NM_145056 147906 0.090484176
AGI_HUM1_OUGO_A_23_P360983 LOC91942 Hypothetical protein LOC91942 NM_174889 91942 0.090484176
AGI_HUM1_OUGO_A_23_P364056 NM_001011724 0.090484176
AGI_HUM 1_OLIGO_A_23_P369047 ENST0000032498: 0.090484176
AGI_HU l_OUGO_A_23_P369994 DCAMKLl Doublecortin and CaM kinase-like 1 NM_004734 9201 0.090484176
AGI_HUM l_OLIGO_A_23_P374288 CASC3 Cancer susceptibility candidate 3 NM_007359 22794 0.090484176
AGI_HUM1_OLIGO_A_23_P37505 DYX1C1 Dyslexia susceptibility 1 candidate 1 NM_130810 161582 0.090484176
AGI_HU l_OLIGO_A_23_P37514 D FZP434H132 DKFZP434H132 protein BC011905 56905 0.090484176
AG I_H U M l_OU GO_A_23_P387374 HSD17B1 Hydroxysteroid (17-beta) dehydrogenase 1 BC033110 3292 0.090484176
AGI_HUM1_OLIGO_A_23_P389907 ATXN2 Ataxin 2 NM_002973 6311 0.090484176
AGI_HUMl_OUGO_A_23_P394216 KIAA0329 KIAA0329 NM_014844 9895 0.090484176
AGI_HUMl_OUGO_A_23_P395566 FBX031 F-box protein 31 NM_024735 79791 0.090484176
AGI_HUM1_OLIGO_A_23_P407142 LUZP1 Leucine zipper protein 1 NM_033631 7798 0.090484176
AGI_HUM1_OLIGO_A_23_P409945 OAZ1 Ornithine decarboxylase antizyme 1 NM_004152 4946 6.090484176
AGI_HUM l_OUGO_A_23_P41314 FU Coagulation factor XI (plasma thromboplastin antecedent) NM_000128 , 2160 0.090484176
AG1_HUM 1_0UG0_A_23_P416581 GNAZ Guanine nucleotide binding protein (G protein), alpha z polypeptide NM_002073 2781 0.090484176
AGI_HUM 1_OLIGO_A_23_P42036 DJ12208.2 Hypothetical protein dJ 12208.2 NM_020466 57226 0.090484176
AGI_HUM 1_OLIGO_A_23_P42042 D312208.2 Hypothetical protein dJ 12208.2 NM_020466 57226 0.090484176
AGI_HU l_OLIGO_A_23_P421638 KIAA1190 Hypothetical protein KIAA1190 NM_145166 92999 0.090484176
AGI_HU l_OLIGO_A_23_P42975 PRKAR2B Protein kinase, cAMP-dependent, regulatory, type II, beta NM_002736 5577 0.090484176
AGI_HUM1_OUGO_A_23_P43276 GPR124 G protein-coupled receptor 124 NM_032777 25960 0.090484176
AGl_HU l_OLIGO_A_23_P43566 NDUFA8 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8, 19kDa NM_014222 4702 0.090484176
AGI_HUMl_OLIGO_A_23_P44291 CRTAP Cartilage associated protein NM_006371 10491 0.090484176
AGI_HUMl_OLIGO_A_23_P48717 NPC2 Niemann-Pick disease, type C2 NM_006432 10577 0.090484176
AGI_HUM l_OLIGO_A_23_P53588 WNT5B Wingless-type MMTV integration site family, member 5B NM_030775 81029 0.090484176
AGI_HUM1_0L1G0_A_23_P54576 KIFC3 Kinesin family member C3' NM_005550 3801 0.090484176
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUMl_OUGO_A_23_P5568 MGC5391 Hypothetical protein MGC5391 NM_032740 84826 0.090484176 AGI_HUM1_OUGO_A_23_P60146 PDGFRL Platelet-derived growth factor receptor-like NM_006207 5157 0.090484176 AGI_HUM1_OLIGO_A_23_P61406 SHC3 Chromosome 9 open reading frame 33 NM_016848 53358 0.090484176 AGI_HUM1_OLIGO_A_23_P64489 RIC-8 Likely ortholog of mouse synembryn NM_021932 60626 0.090484176
Pleckstrin homology domain containing, family A (phosphoinositide binding
AGI_HUM1_OLIGO_A_23_P67360 PLEKHA4 specific) member 4 NM_020904 57664 0.090484176 AGI_HUM1_0LIG0_A_23_P69267 DKFZP5640243 DKFZP5640243 protein NM_015407 25864 0.090484176 AGI_HUM l_OUGO_A_23_P69497 TNA Tetranectin (plasminogen binding protein) NM_003278 7123 0.090484176 AGI _HUM1_OLIGO_A_23_P71091 GCC1 GRIP and coiled-coil domain containing 1 NM_024523 79571 0.090484176
AGI_HUM1_OLIGO_A_ 23_P7144 CXCL1 Chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha) NM_001511 2919 0.090484176 AGI_HUM1_OUGO_A. 23_P74349 CDCA1 Cell division cycle associated 1 NM_145697 83540 0.090484176 AGI_HUM1_0UG0_A. 23_P82068 N0L7 Nucleolar protein 7, 27kDa NM_016167 51406 0.090484176 AGI_HUMl_OI_IGO_A_ 23_P8281 IFNGR1 Interferon gamma receptor 1 NM_000416 3459 0.090484176 AGI_HUMl_OUGO_A. ,23_P84018 PPIC Peptidylprolyl isomerase C (cyclophilin C) NM_000943 5480 0.090484176 AGI_HUMl_OLIGO_A. 23_P84070 HDCMA18P HDCMA18P protein NM_016648 51574 0.090484176 AGI HUM1 OUGO A 23_P88559 UPC Lipase, hepatic NM_000236 3990 0.090484176
Glucosaminyl (N-acetyl) transferase 1, core 2 (beta-l,6-N-
AGI_HUM1 OLIGO. A_23. P9232 GCNT1 acetylglucosaminyltransferase) NM_001490 2650 0.090484176 AGI_HU 1 OUGO. A_23_ P98350 BIRC3 Baculoviral IAP repeat-containing 3 NM_001165 330 0.090484176 AGI_HUM1 .OUGO. A_24. P106624 MEOX2 Mesenchyme homeo box 2 (growth arrest-specific homeo box) NM_005924 4223 0.090484176 AGI_HUM1 OUGO. A_24. P115621 ENST0000037321! 0.090484176 AGI_HUM1 OUGO. A_24_ PI 16535 MMP15 Matrix metalloproteinase 15 (membrane-inserted) NM_002428 4324 0.090484176 AGI_HUM1 .OUGO. A_24. P12435 NCOA7 Nuclear receptor coactivator 7 NM_181782 135112 0.090484176 AGL.HUM1 .OLIGO..A_24. .P131522 ANTXR1 Anthrax toxin receptor 1 NM_032208 84168 0.090484176 AGI_HUM1 OUGO. A_24. P143843 ENST0000034268f 0.090484176 AGI_HUM1 .OUGO. A_24. P144784 HILS1 Spermatid-specific linker histone Hl-like protein NM_194072 373861 0.090484176 AGI_HUM1 .OUGO. A_24. P148373 EN5T0000037401'. 0.090484176 AGI_HUM1 OUGO. A_24_ P149124 C5orfl3 Chromosome 5 open reading frame 13 NM_004772 9315 0.090484176 AGI_HUM1 OUGO. A_24. P163632 OXR1 Oxidation resistance 1 NM_181354 55074 0.090484176 AGI_HUM1 .OUGO..A_24. .P167473 ARPC3 Actin related protein 2/3 complex, subunit 3, 21kDa NM_005719 10094 0.090484176 AGI_HUM1 .OUGO..A_24. .P17722 KIAA0676 KIAA0676 protein NM_198868 23061 0.090484176 AGI_HUM1 .OUGO..A_24. .P178273 PTK9 PTK9 protein tyrosine kinase 9 NM_198974 5756 0.090484176 AGI_HUM1 .OUGO..A_24. P19S205 ENST0000036142! 0.090484176 AGL.HUM1 .OUGO..A_24. P196774 NUDT1 Nudix (nucleoside diphosphate linked moiety X)-type motif 1 BCO 14395 4521 0.090484176 AGI_HUM1 .OUGO..A_24. .P205130 FNBP1 Formin binding protein 1 NM_015033 23048 0.090484176 AGI_HUM1 .OUGO. A_24. P218587 CRSP6 Cofactor required for Spl transcriptional activation, subunit 6, 77kDa NM_004268 9440 0.090484176 AGI_HUM1 OUGO. A_24. P22436 MGC4606 Hypothetical protein MGC4606 NM_024516 79447 0.090484176 AGI_HUM1 .OUGO. A_24. P234871 A_24_P234871 0.090484176 AGI_HUM1 .OUGO..A_24. .P251899 CSNK1A1 Casein kinase 1, alpha l NM_001892 1452 0.090484176 AGI_HUM1 .OUGO..A_24. P252846 LOC119710 Hypothetical protein BC009561 NM_138787 119710 0.090484176 AGI_HUM1 .OUGO. -A_24. .P264644 A_24_P264644 0.090484176 AGI_HUM1 .OUGO..A_24. P281730 A_24_P281730 0.090484176 AGI_HUM1 .OUGO. A_24. P298545 MGC42415 Hypothetical protein MGC42415 NM_153363 168417 0.090484176 AGI_HUM1 .OUGO..A_24. .P29885 NOV Nephroblastoma overexpressed gene NM_002514 4856 0.090484176 AGI_HU 1 .OUGO. A_24. P30670 WBP4 WW domain binding protein 4 (formin binding protein NM_007187 11193 0.090484176 AGI_HU 1 .OUGO. A_24. P320328 PC4 Activated RNA polymerase II transcription cofactor 4 NM_006713 10923 0.090484176 AGI_HUM1 OUGO. A_24. P32836 A_24_P32836 0.090484176 AGI_HUM1 .OUGO. A_24. P330668 KIAA1970 KIAA1970 protein NM_019116 124454 0.090484176 AGI_HUM1 OLIGO. A_24. P339416 KIAA1001 Arylsulfatase G NM_014960 22901 0.090484176 AGI_HUM1 .OUGO..A_24. .P339611 PDCD5 Programmed cell death 5 NM_004708 9141 0.090484176 AGI_HUM1 .OUGO..A_24. .P340066 ELF4 E74-like factor 4 (ets domain transcription factor) NM_001421 2000 0.090484176 AGI_HUM1 .OUGO. A_24. P345377 GOLPH3L Golgi phosphoprotein 3-like NM_018178 55204 0.090484176 AGI HUM1 OUGO_ A_24_ P346269 THC2342624 0.090484176
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUMl_OUGO_A_24_P348649 NDUFA1 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5kDa NM_004541 4694 0.090484176
AGI_HUMl_OLIGO_A_24_P351435 CRBN Cereblon NM_016302 51185 0.090484176
AGI_HUMl_OUGO_A_24_P376391 PLXND1 Plexin Dl NM_015103 23129 0.090484176
AGI_HU 1_OUGO_A_24_P378302 NM_001040150 0.090484176
AGI_HUM1_OUGO_A_24_P379820 ITM2C Integral membrane protein 2C NM_030926 81618 0.090484176
Pleckstrin homology domain containing, family A (phosphoinositide binding
AGI_HUM1_OUGO_A_24_P408047 PLE HA4 specific) member 4 NM_020904 57664 0.090484176
AGI_H U M l_OU GO_A_24_P 1339 XM_930460 0.090484176
AGI_HUMl_OUGO_A_24_P43588 MAD2L1BP MAD2L1 binding protein NM_001003690 9587 0.090484176
AGI_HUMl_OUGO_A_24_P478556 CDNA clone IMAGE:4796690, partial cds BC030102 0.090484176
AGI_HUMl_OUGO_A_24_P49597 ENST0000029975f 0.090484176
AGI_HUMl_OUGO_A_24_P592591 THC2270231 0.090484176
AGI_HU 1_OLIGO_A_24_P59607 ENST0000037919; 0.090484176
AGI_HUM1_OUGO_A_24_P605612 THBS2 Thrombospondin 2 NM_003247 7058 0.090484176
AGI_HUMl_OUGO_A_24_P62521 PSEN2 Presenilin 2 (Alzheimer disease 4) NM_000447 5664 0.090484176
Dopachrome tautomerase (dopachrome delta-isomerase, tyrosine-related protein
AGI_HUMl_OUGO_A_24_P68381 DCT 2) NM_001922 1638 0.090484176
AGI_HUM1_OUGO_A_24_P6850 A_24_P6850 0.090484176
AGI_HUMl_OUGO_A_24_P73599 IL16 Interleukin 16 (lymphocyte chemoattractant factor) NM_172217 3603 0.090484176
AGI_HUMl_OUGO_A_24_P832156 C9orflOOS Chromosome 9 open reading frame 10 opposite strand NM_198841 158293 0.090484176
AGI_HUM1_OUGO_A_24_P920447 C14orfl32 Chromosome 14 open reading frame 132 NM_020215 56967 0.090484176
AG1_HUM1_OLIGO_A_24_P940006 EFNB3 Ephrin-B3 NM_001406 1949 0.090484176
AGI_HUM1_OUGO_A_32_P101860 XM_930086 0.090484176
Full-length cDNA clone CS0DC003YA14 of Neuroblastoma Cot 25-normalized of
AGI_HUM1_OUGO_A_32_P108722 Homo sapiens (human) AK127572 0.090484176
AGI_HUM1_0L1G0_A_32_P113404 A_32_P 113404 0.090484176
AGI_HUM l_OUGO_A_32_ 12S338 FAM43B Family with sequence similarity 43, member B NM_207334 163933 0.090484176
AGI_HUMl_OUGO_A_32_P1445 PTPN2 Protein tyrosine phosphatase, non-receptor type 2 NM_080423 5771 0.090484176
AGI_HUM1_OUGO_A_32_P150040 Full-length cDNA clone CS0DF003YF10 of Fetal brain of Homo sapiens (human) CR606969 0.090484176
AGI_HUMl_OLIGO_A_32_P161432 CBWD1 COBW domain containing 1 NM_172003 55871 0.090484176
AGI_HU l_OLIGO_A_32_P169131 ALG1 Asparagine-linked glycosylation 1 homolpg (yeast, beta-l,4-mannosyltransferase) NM_019109 56052 0.090484176
AGI_HUM l_OUGO_A_32_P 172141 CDON Cell adhesion molecule-related/down-regulated by oncogenes NM_016952 50937 0.090484176
AGI_HUM1_OLIGO_A_32_P178099 EB386378 0.090484176
AGI_HUMl_OUGO_A_32_P179676 TOB2 Transducer of ERBB2, 2 NM_016272 10766 0.090484176
AGI_HUM1_OLIGO_A_32_P188860 IL17RD Interleukin 17 receptor D AK125591 54756 0.090484176
AGI_HUM1_OUGO_A_32_P229065 NM_001031800 0.090484176
AGI_HUMl_OLIGO_A_32_P53524 BC092429 0.090484176
AGI_HUMl_OLIGO_A_32_P59S49 GFRA1 GDNF family receptor alpha 1 NM_14S793 2674 0.090484176
AGI_H U M 1_0 LIGO_A_32_P65395 XM_209655 0.090484176
AGI_HUMl_OUGO_A_32_P78285 XM_938617 0.090484176
AGI_HUMl_OUGO_A_32_P79396 PBEF1 Pre-B-cell colony enhancing factor 1 NM_005746 10135 0.090484176
AGI_HUM1_OUGO_A_32_P80089 ENST0000034606: 0.090484176
AGI_HU 1_OUGO_A_32_P84707 THC2308802 0.090484176
AGI_HUMl_OUGO_A_32_P84846 LOC163131 Hypothetical BC331191_1 NM_001005851 163131 0.090484176
AGI_HUM1_OUGO_A_32_P94087 NM_001011538 0.090484176
AGI_HUM1_OUGO_A_32_P99902 MGC29937 Hypothetical protein MGC29937 NM_144597 123207 0.090484176
AGI_HUM1_OUGO_A_24_P110967 LOC115294 Similar to hypothetical protein FU10883 NM_052937 115294 0.090566641
AGI_HUM1_OUGO_A_23_P208961 MUM1 Melanoma associated antigen (mutated) 1 NM_032853 84939 0.090776283
AGI_HUM1_OUGO_A_23_P81103 SFRP2 Secreted frizzled-related protein 2 NM_003013 6423 0.090875466
AGI_HUMl_OUGO_A_32_P62997 TOPK T-LAK cell-originated protein kinase NM_018492 55872 0.090875466
AGI_HUM1_OLIGO_A_23_P433820 THAP8 THAP domain containing 8 NM_152658 199745 0.091250181
AGI_HUMl_OLIGO_A_24_P311694 MAML1 Mastermind-like 1 (Drosophila) NMJ314757 9794 0.091250181
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_H UM 1_OUGO_A_24_P50829 TRPM7 Transient receptor potential cation channel, subfamily M, member 7 NM_017672 54822 0.091250181
AGI_HUM1_OUGO_A_32_P101301 USP39 Ubiquitin specific protease 39 ' NM_006590 10713 0.091250181
AGI_HUM1_OUGO_A_23_P100711 PMP22 Peripheral myelin protein 22 NM_000304 5376 0.091253805
AGI_HUMl_OUGO_A_23_P145463 SLC35B3 Solute carrier family 35, member B3 NM_015948 51000 0.091522184
AGl_HUMl_OUGO_A_23_P419624 BLCAP Bladder cancer associated protein NM_006698 10904 0.091522184
AGI_HU 1_OLIGO_A_23_P400794 ENST0000031163( 0.092872595
AGI_HU 1_0LIG0_A_23_P86884 SART1 Squamous cell carcinoma antigen recognised by T cells NM_005146 9092 0.092872595
AGI_HU l_OUGO_A_24_P419211 MTMR6 yotubularin related protein 6 NM_004685 9107 0.092872595
AGI_HUMl_OI_IGO_A_23_P12911 Cllorf24 Chromosome 11 open reading frame 24 NM_022338 53838 0.093105978
AGI_HU l_OUGO_A_23_P32861 CGI-07 CGI-07 protein NM_015938 51068 0.093105978
AGI_HUMl_OUGO_A_23_P47665 HBE1 Hemoglobin, epsilon 1 NM_005330 3046 0.093105978
AGI_HUM1_OUGO_A_23_P51202 ZNF436 Zinc finger protein 436 NM_030634 80818 0.093105978
AGI_HUMl_OUGO_A_23_P7229 RPL34 Ribosomal protein L34 NM_033625 6164 0.093105978
AGI_HUMl_OLIGO_A_23_P8513 SNX10 Sorting nexin 10 NM_013322 29887 0.093105978
AGI_HUM1_OUGO_A_23_P157038 MGC40499 Hypothetical protein GC40499 NM_1S2755 245812 0.093210689
AGI_HUMl_OUGO_A_24_P246825 THC2295607 0.093210689
AGI_HUMl_OUGO_A_32_P322S4 COL6A1 Collagen, type VI, alpha 1 NM_001848 1291 0.093210689
AGI_HUM1_OUGO_A_23_P124003 P2RX2 Purinergic receptor P2X, ligand-gated ion channel, 2 NM_170683 22953 0.093708677
AGI_HUM1_OUGO_A_23_P101871 FBX017 F-box protein 17 NM_024907 115290 0.093887665
AGI_HU l_OUGO_A_23_P111132 HSPA1A Heat shock 70kDa protein 1A NM_005345 3303 0.093887665
AGI_HUMl_OLIGO_A_23_P112289 TMOD1 Tropomodulin 1 NM_003275 7111 0.093887665
AGI_HUM l_OLIGO_A_23_Pl 14952 TMEM9 Transmembrane protein 9 NM_016456 252839 0.093887665
AGI_HUMl_OLIGO_A_23_P115356 AKR7A2 Aldo-keto reductase family 7, member A2 (aflatoxin aldehyde reductase) NM_003689 8574 0.093887665
AGI_HUM l_OUGO_A_23_Pl 15460 RPL22 Ribosomal protein L22 NM_000983 6146 0.093887665
AGI_HU l_OLIGO_A_23_P115922 EIF4EBP2 Eukaryotic translation initiation factor 4E binding protein 2 NM_004096 1979 0.093887665
AGI_HUM1_OUGO_A_23_P117082 HEBP1 Heme binding protein 1 NM_015987 50865 0.093887665
AGI_HUMl_OUGO_A_23_P117654 MY05A Myosin VA (heavy polypeptide 12, myoxin) NM_000259 4644 0.093887665
AGI_HUM l_OUGO_A_23_Pl 18493 TOM1L1 Target of mybl-like 1 (chicken) NM_005486 10040 0.093887665
AGI_HUMl_OUGO_A_23_P119562 DF D component of complement (adipsin) NM_001928 1675 0.093887665
AGI_HUM1_OUGO_A_23_P120103 KCNS3 Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 3 NM_002252 3790 0.093887665
AGI_HUMl_OUGO_A_23_P128956 ZFYVE1 Zinc finger, FYVE domain containing 1 NM_021260 53349 0.093887665
AGI_HUMl_OUGO_A_23_P1331 COL13A1 Collagen, type XIII, alpha 1 NM_005203 1305 0.093887665
AGI_HUMl_OUGO_A_23_P139476 CD63 CD63 antigen (melanoma 1 antigen) NM_001780 967 0.093887665
AGI_HUMl_OUGO_A_23_P147514 D FZp547E052 Hypothetical protein D FZp547E052 BC062636 84236 0.093887665
AGI_HUM1_OUGO_A_23_P157051 AP4M1 Adaptor-related protein complex 4, mu 1 subunit NM_004722 9179 0.093887665
AGI_HUM1_OUGO_A_23_P162795 SUGT1 SGT1, suppressor of G2 allele of SKP1 (S. cerevisiae) NM_006704 10910 0.093887665
Sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and
AGI_HUM1_OUGO_A_23_P165608 SEMA4F short cytoplasmic domain, (semaphorin) 4F NM_004263 10505 0.093887665
AGI_HUM1_OUGO_A_23_P201963 PARD3 Par-3 partitioning defective 3 homolog (C. elegans) AF196185 56288 0.093887665
AGI_HUM1_OLIGO_A_23_P211015 C21orf91 Chromosome 21 open reading frame 91 NM_017447 54149 0.093887665
AGI_HU l_OUGO_A_23_P21382 LAMB2 Laminin, beta 2 (laminin S) NM_002292 3913 0.093887665
AGI_HUM1_OUGO_A_23_P253052 CD99L2 CD99 antigen-like 2 NMJ331462 83692 0.093887665
AGI_HUMl_OUGO_A_23_P254165 RAI2 Retinoic acid induced 2 NM_021785 10742 0.093887665
AGI_HUMl_OUGO_A_23_P254978 TATDN1 TatD DNase domain containing 1 NM_032026 83940 0.093887665
AGI_HUMl_OUGO_A_23_P258666 MRNA, endogenous retrovirus BC021996 0.093887665
AGI_HUMl_OUGO_A_23_P26184 DET1 De-etiolated 1 NM_017996 55070 0.093887665
AGI_HUMl_OUGO_A_23_P26954 VAT1 Vesicle amine transport protein 1 homolog (T californica) NM_006373 10493 0.093887665
AGI_HUM l_OUGO_A_23_P28434 VAMP8 Vesicle-associated membrane protein 8 (endobrevin) NM_003761 8673 0.093887665
AGI_HUM1_OUGO_A_23_P304171 ENST0000027358; 0.093887665
AGI_HUMl_OUGO_A_23_P313645 MAP3K2 Mitogen-activated protein kinase kinase kinase 2 NM_006609 10746 0.093887665
AGI_HUM1_OUGO_A_23_P321377 FU38984 Hypothetical protein FU38984 NM_152374 127703 0.093887665
AGI_HUM1_OLIGO_A_23_P329890 MGC17839 Hypothetical protein MGC17839 NM_174926 219902 0.093887665
AGI_HUM1_OLIGO_A_23_P334709 FKBP9 FK506 binding protein 9, 63 kDa NM_007270 11328 0.093887665
AGI_HUM1_OUGO_A_23_P339480 HAT1 Histone acetyltransferase 1 NM_003642 8520 0.093887665
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
o
Quinolinate phosphoribosyltransferase (nicotinate-nucleotide pyrophosphorylase
O
r~ AGI_HUMl_OUGO_A_23_P34233 QPRT (carboxylating)) NM_014298 23475 0.093887665
AGI_HUM1_OUGO_A_23_P356004 CSEN Calsenilin, presenilin binding protein, EF hand transcription factor NM_013434 30818 0.093887665 o
AGI_HU l_OUGO_A_23_P391689 PCP2 Purkinje cell protein 2 CR602285 126006 0.093887665
AGI_HUMl_0LIGO_A_23_P401 CENPF Centromere protein F, 350/400ka (mitosin) NM_016343 1063 0.093887665
AGI_HUM1_OUGO_A_23_P402610 PFAS Phosphoribosylformylglycinamidine synthase (FGAR amidotransferase) N J312393 5198 0.093887665
AGI_HUM1_OUGO_A_23_P408996 OACTl O-acyltransferase (membrane bound) domain containing 1 AK131269 154141 0.093887665
AGI_HUMl_OUGO_A_23_P411953 PYG02 Pygopus homolog 2 (Drosophila) NM_138300 90780 0.093887665
AGI_HUMl_OUGO_A_23_P4212 H0XB13 Homeo box B13 N _006361 10481 0.093887665
AGI_HU l_OUGO_A_23_P432573 MRGPRF AS-related GPR, member F NM_145015 219928 0.093887665
AGI_HUMl_OUGO_A_23_P44684 ECT2 Epithelial cell transforming sequence 2 oncogene NM_018098 1894 0.093887665
AGI_HUM1_OUGO_A_23_P502174 D2LIC Dynein 2 light intermediate chain NM_015522 51626 0.093887665
AGI_HUMl_OUGO_A_23_P51346 ENST0000037657; 0.093887665
AGI_HUMl_OUGO_A_23_PS6328 PLVAP Plasmalemma vesicle associated protein NM_031310 83483 0.093887665
AGI_HUMl_OUGO_A_23_P56938 REL V-rel reticuloendotheliosis viral oncogene homolog (avian) NM_002908 5966 0.093887665
AGI_HUMl_OLIGO_A_23_P59921 PC4 Activated RNA polymerase II transcription cofactor 4 N _006713 10923 0.093887665
AGI_HUMl_OUGO_A_23_P66766 RIP RPA interacting protein NM_032308 84268 0.093887665
AGI_HUMl_OUGO_A_23_P69121 SIAH2 Seven in absentia homolog 2 (Drosophila) NMJ305067 6478 0.093887665
AGI_HUMl_OUGO_A_23_P84836 NPEPPS Aminopeptidase puromycin sensitive NM_006310 9520 0.093887665
AGI_HUMl_OUGO_A_23_P98218 HSPC148 Hypothetical protein HSPC148 NM_016403 51503 0.093887665
AGI_HUMl_OUGO_A_24_P121631 MGC13138 Hypothetical protein MGC13138 NM_033410 92595 0.093887665
AGI_HU l_OUGO_A_24_P123658 ENST0000037287: 0.093887665
AGI_HUM1_OUGO_A_24_P150428 FU30707 Hypothetical protein FU30707 NM_145019 220108 0.093887665
AGI_HUMl_OUGO_A_24_P175989 VPS29 Vacuolar protein sorting 29 (yeast) NM_057180 51699 0.093887665
AGI_HUMl_OUGO_A_24_P189458 C10orf86 Chromosome 10 open reading frame 86 NM_017615 54780 0.093887665
AGI_HUM1_OUGO_A_24_P191067 NM_001009566 0.093887665
Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole CD
AGI_HUM1_OUGO_A_24_P200427 PAICS succinocarboxamide synthetase NM_006452 10606 0.093887665 CD
AGI_HUM1_OUGO_A_24_P203479 MSH3. MutS homolog 3 (E. coli) NM_002439 4437 0.093887665
AGI_HUMl_OUGO_A_24_P213487 LAT1-3TM LAT1-3TM protein AF271775 81893 0.093887665
AGI_HU l_OUGO_A_24_P229728 A_24_P229728 0.093887665
AGI_HUMl_OLIGO_A_24_P271363 CDS2 CDP-diacylglycerol synthase (phosphatidate cytidylyltransferase) 2 NM_003818 8760 0.093887665
AGI_HUMl_OUGO_A_24_P277657 GMPR Guanosine monophosphate reductase NM_006877 2766 0.093887665
AGI_HUMl_OLIGO_A_24_P281395 ENST0000037228I 0.093887665
AGI_HUM1_OUGO_A_24_P286013 HIP2 Huntingtin interacting protein 2 N _005339 3093 0.093887665
AGI_HUM1_OUGO_A_24_P296808 FU 10781 Hypothetical protein FU10781 NM_018215 55228 0.093887665
AGI_HUM1_OUGO_A_24_P296907 THAP8 THAP domain containing 8 N _152658 199745 0.093887665
AGI_HUMl_OLIGO_A_24_P341426 A_24_P341426 0.093887665
AGI_HUM1_OLIGO_A_24_P409420 A_24_P409420 0.093887665
AGI_HUMl_OUGO_A_24_P466374 EYA3 Eyes absent homolog 3 (Drosophila) BX648945 2140 0.093887665
AGI_HUMl_OUGO_A_24_P48177 SIAT4B Sialyltransferase 4B (beta-galactoside alpha-2,3-sialyltransferase) AK127322 6483 0.093887665
AGI_HUMl_OLIGO_A_24_P511877 CDNA FU46881 fis, clone UTERU3015647, moderately similar to Embigin precursor AK128714 0.093887665
AGI_HUM1_OLIGO_A_24_P782308 NEDD4L Neural precursor cell expressed, developmentally down-regulated 4-like CR596491 23327 0.093887665
90 AGI_HUM1_OLIGO_A_24_P844100 A_24_P844100 0.093887665
90 AGI_HUM1_0UG0_A_24_P944827 APG7L APG7 autophagy 7-like (S. cerevisiae) AL122075 10533 0.093887665
AGI_HUM1_OUGO_A_24_P95029 TAX1BP1 Taxi (human T-cell leukemia virus type I) binding protein 1 NM_006024 8887 0.093887665
AGI_HU l_OUGO_A_32_P112279 NM_001039690 0.093887665
O AGI_HUM1_OUGO_A_32_P116058 NR_002800 0.093887665
o AGI_HUM1_OUGO_A_32_P116203 NCF1 Neutrophil cytosolic factor 1 (47kDa, chronic granulomatous disease, autosomal 1) NM_000265 4687 0.093887665
AGI_HUMl_OLIGO_A_32_P163469 NFE2L1 Nuclear factor (erythroid-derived 2)-like 1 AL833530 4779 0.093887665
AGI_HUM 1_0LIG0_A_32_P 171232 A_32_P171232 0.093887665
AGI_HUMl_OUGO_A_32_P184367 RPL10 Ribosomal protein L10 NM_006013 6134 0.093887665
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
o
AGl_HUMl_OLIGO_A_32_P225355 CPEB2 Cytoplasmic polyadenylation element binding protein 2 NM_182485 132864 0.093887665
O AGI_HUM1_OLIGO_A_32_P230736 Hypothetical LOC389033 XM_374010 389033 0.09388766S
AGI_HUMl_OUGO_A_32_P2333 PC4 Activated RNA polymerase II transcription cofactor 4 NM_006713 10923 0.093887665 o
AGI_HUMl_OUGO_A_32_P32179 FU44670 FU44670 protein AK057056 375096 0.093887665
AGI_HU l_OUGO_A_32_P32722 LOC255458 Hypothetical protein LOC255458 CR603845 255458 0.093887665
AGI_HUM1_OUGO_A_32_P460399 MRNA full length insert cDNA clone EUROIMAGE 2362292 AL365520 0.093887665
AGI_HU l_OLIGO_A_32_P5821S ENST0000036805' 0.093887665
AGI_HUMl_OUGO_A_32_P6442 THC2406192 0.093887665
AGI_HUMl_OUGO_A_32_P83845 HEY1 Hairy/enhancer-of-split related with YRPW motif 1 NM_012258 23462 0.093887665
AGl_HU l_OUGO_A_23_P49279 LOC388272 Similar to RIKEN cDNA 4921524Π7 NM_001001436 388272 0.093920232
AGI_HUMl_OLIGO_A_23_P78134 NM_001014764 0.093920232
AGI_HUMl_OLIGO_A_23_P92441 MAD2L1 MAD2 mitotic arrest deficient-like 1 (yeast) NM_002358 4085 0.093920232
AGI_HUM1_0L1G0_A_24_P237778 MAN1C1 Mannosidase, alpha, class 1C, member 1 NM_020379 57134 0.093920232
AGI_HUM1_OUGO_A_24_P358205 A_24_P358205 0.093920232
AGI_HUM 1_0UG0_A_24_P47467 MGC5508 Hypothetical protein MGC5508 NM_024092 79073 0.093920232
AGI_HUMl_OUGO_A_23_P216949 PDCL Phosducin-like NM_005388 5082 0.094362947
AGI_HUM1_OLIGO_A_23_P154306 TANK TRAF family member-associated NFKB activator NM_004180 10010 0.095027623
AGI_HUMl_OUGO_A_23_P213385 BASP1 Brain abundant, membrane attached signal protein 1 NM_006317 10409 0.095027623
AGI_HUMl_OLIGO_A_23_P251387 REPS2 RALBP1 associated Eps domain containing 2 NM_004726 9185 0.095027623
AGI_HUMl_OUGO_A_23_P254733 MLF1IP LFl interacting protein NM_024629 79682 0.095027623
AGI_HUMl_OLIGO_A_23_P29747 RPL23A Ribosomal protein L23a NM_000984 6147 0.095027623
AGI_HUMl_OUGO_A_23_P371613 CHCHD1 Coiled-coil-helix-coiled-coil-helix domain containing 1 NM_203298 118487 0.095027623
AGI_HUM1_OUGO_A_23_P434900 C16orf34 Chromosome 16 open reading frame 34 NM_144570 90861 0.095027623
AGI_HUMl_OUGO_A_23_P65262 PFAAP5 Phosphonoformate immuno-associated protein 5 NM_033111 10443 0.095027623
AGI_HUM1_OUGO_A_23_P71S70 0SR2 Odd-skipped related 2 (Drosophila) NM_053001 116039 0.095027623
AGI_HU l_OUGO_A_24_P125311 A_24_P125311 0.095027623
AGI_HUMl_OLIGO_A_24_P15765 F N2 Formin 2 AK098605 56776 0.095027623
AGI_HUM1_OUGO_A_24_P287503 ZFYVE1 Zinc finger, FYVE domain containing 1 NM_021260 53349 0.095027623
TAF2 RNA polymerase II, TATA box binding protein (TBP)-associated factor,
AGI_HU l_OUGO_A_24_P385119 TAF2 150kDa NM_003184 6873 0.095027623 co
AGI_HUMl_OUGO_A_24_P58899 A_24_P58899 0.095027623
AGI_HU l_OUG0_A_24_P943843 CDNA FU30141 fis, clone BRACE2000148 AK124515 0.095027623
AGI_HUMl_OUGO_A_321P113193 ZNF592 Zinc finger protein 592 NM_014630 9640 0.095027623
AGI_HUM1_0LIG0_A_32_P141445 MGC34796 SPR pseudogene BC034822 414927 0.095027623
AGI_HUM1_OUGO_A_23_P140960 NDUFAB1 NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kDa N _005003 4706 0.095262298
AGI_HUM l_OUGO_A_23_P214091 LYPLA1 Lysophospholipase I NM_006330 10434 0.095262298
AGI_HUMl_OUGO_A_23_P315933 WBSCR21 Williams Beuren syndrome chromosome region 21 NM_031295 83451 0.095262298
AG1_HUM1_OUGO_A_23_P50108 KNTC2 Kinetochore associated 2 NM_006101 10403 0.095262298
AGI_HUM1_OUGO_A_23_P6674 LXN Latexin NM_020169 56925 0.095262298
AGI_HUM1_OUGO_A_23_P88810 MLYCD Malonyl-CoA decarboxylase NM_012213 23417 0.095262298
AGI_HUM1_OUGO_A_24_P124370 PARVA Parvin, alpha NM_018222 55742 0.095262298
AGI_HUMl_OUGO_A_32_P96752 S0X4 SRY (sex determining region Y)-box 4 AW946823 6659 0.095262298
AGI_HUMl_OLIGO_A_23_P375165 FU35767 FU35767 protein NM_207459 400629 0.095338015
*0 AGI_HUM1_OUGO_A_24_P170887 FU20989 Hypothetical protein FU20989 NM_023080 65265 0.095436493
90 AGI_HU 1_OUGO_A_23_P109001 KIAA0406 KIAA0406 gene product NM_014657 9675 0.095538395 90 AGI_HUM1_OUGO_A_23_P202219 FAM26B Family with sequence similarity 26, member B NM_015916 51063 0.095538395
AGI_HU 1_OUGO_A_23_P22460 BIRC4 Baculoviral IAP repeat-containing 4 NM_001167 331 0.095538395
AGI_HU 1_OUGO_A_23_P401076 SUSD3 Sushi domain containing 3 NM_145006 203328 0.095538395
O AGI_HU 1_OUGO_A_23_P63026 LGALS8 Lectin, galactoside-binding, soluble, 8 (galectin 8) NM_006499 3964 0.095538395
AGI_HUM1_OLIGO_A_23_P96350 PRAF2 PRA1 domain family, member 2 NM_007213 11230 0.095538395 o MADS box transcription enhancer factor 2, polypeptide B (myocyte enhancer factor
AGI_HUM1_OUGO_A_24_P282013 MEF2B 2B) A 0S7161 4207 0.095538395
AGr_HUMl_OLlGO_A_24_P943000 P0P1 Processing of precursor 1, ribonuclease P/MRP subunit (S. cerevisiae) D31765 10940 0.095538395
AGI_HUM1_OUGO_A_23_P154037 A0X1 Aldehyde oxidase 1 NM_001159 316 0.09565787
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUMl_OUGO_A_23_P334282 BMP2K BMP2 inducible kinase NM_017593 55589 0.095822416
AGI_HUMl_OUGO_A_23_P38864 RABAC1 Rab acceptor 1 (prenylated) NM_006423 10567 0.095822416
AGI_HUMl_OUGO_A_23_P81898 UBD Ubiquitin D NM_006398 10537 0.095822416
AGI_HUM1_0L1G0_A_24_P196592 MMP28 Matrix metalloproteinase 28 NM_024302 79148 0.095866261
AGI_HU 1_OUGO_A_32_P116113 DI02 Deiodinase, iodothyronine, type II CN479762 1734 0.095866261
AGI_HUM l_OLIGO_A_24_P349547 A_24_P349547 0.096048224
AGI_HUM1_OUGO_A_23_P309619 PLEKHM1 Pleckstrin homology domain containing, family M (with RUN domain) member 1 AK123704 9842 0.096145456
AGI_HUMl_OLIGO_A_23_P396858 FZD8 Frizzled homolog 8 (Drosophila) NM_031866 8325 0.096145456
AGI_HUMl_OUGO_A_23_P399169 HICl Hypermethylated in cancer 1 NM_006497 3090 0.096145456
AGI_HUMl_OUGO_A_23_P58117 ShrmL Shroom-related protein NM_020859 57619 0.096145456
AGI_HUM1_OUGO_A_23_P88470 TRPM7 Transient receptor potential cation channel, subfamily M, member 7 NM_017672 54822 0.096145456
AGI_HUMl_OUGO_A_24_P344961 A OT Angiomotin NM_13326S 154796 0.096145456
AGI_HUM1_OUGO_A_23_P140654 THC2375798 0.096332895
AGI_HUMl_OUGO_A_23_P148629 EIF1AY Eukaryotic translation initiation factor 1A, Y-linked NM_004681 9086 0.096332895
AGI_HUM1_OUGO_A_23_P163306 CGNL1 Cingulin-like 1 NM_032866 84952 0.096332895
AGI_HUMl_OLIGO_A_23_P168167 C6orfl68 Chromosome 6 open reading frame 168 NM_032511 84553 0.096332895
AGI_HUMl_OLIGO_A_23_P18317 SLC41A3 Solute carrier family 41, member 3 NM_017836 54946 0.096332895
AGI_HUMl_OUGO_A_23_P212196 OGG1 8-oxoguanine DNA glycosylase NM_016828 4968 0.096332895
AGI_HU l_OUGO_A_23_P212535 D FZP5640123 DKFZP5640123 protein NM_014043 25978 0.09633289S
AGI_HU 1_OLIGO_A_23_P217049 FREQ Frequenin homolog (Drosophila) NM_014286 23413 0.096332895
AGI_HUMl_OUGO_A_23_P217498 GDPD2 Glycerophosphodiester phosphodiesterase domain containing 2 NM_017711 54857 0.096332895
AGI_HUM1_OLIGO_A_23_P301855 LSAMP Limbic system-associated membrane protein NM_002338 4045 0.096332895
AGI_HUM1_OLIGO_A_23_P31315 CBX3 Chromobox homolog 3 (HP1 gamma homolog, Drosophila) NM_016587 11335 0.096332895
AGI_HU l_OUGO_A_23_P325924 ENST0000028867f 0.096332895
AGl_HUMl_OUGO_A_23_P36183 GTF2H1 General transcription factor IIH, polypeptide 1, 62kDa NM_005316 2965 0.096332895
AG1_HUM1_OUGO_A_23_P421011 KAZALD1 Kazal-type serine protease inhibitor domain 1 NM_030929 81621 0.096332895
AGI_HUM1_OUGO_A_23_P500773 MAP3 7 Mitogen-activated protein kinase kinase kinase 7 NM_003188 6885 0.096332895
AGI_HUMl_OUGO_A_23_P9192 ROD1 ROD1 regulator of differentiation 1 (S. pombe) NM_005156 9991 0.096332895
AGI_HUMl_OLIGO_A_24_P124992 PSMA4 Proteasome (prosome, macropain) subunit, alpha type, 4 NM_002789 5685 0.096332895
AGI_HUMl_OLIGO_A_24_P186746 A_24_P186746 0.096332895
AGI_HU 1_OUGO_A_24_P203827 ENST0000031034' 0.096332895
AGI_HU 1_OLIGO_A_24_P307065 XM_933001 0.096332895
AGI_HUMl_OUGO_A_24_P313397 ENST0000021916! 0.096332895
AGI_HU l_OLIGO_A_24_P941166 ZNF425 Zinc finger protein 425 NM_001001661 155054 0.096332895
AGI_HUM1_OLIGO_A_23_P104876 SPA 17 Sperm autoantigenic protein 17 NM_017425 53340 0.096604616
AGI_HUMl_OUGO_A_23_P141946 LTBP4 Latent transforming growth factor beta binding protein 4 NM_003573 8425 0.096604616
AGI_HUMl_OLIGO_A_23_P252536 RPS26 Mitochondrial ribosomal protein S26 NM_030811 64949 0.096604616
AGI_HUM1_OLIGO_A_23_P2705 P2RY5 Purinergic receptor P2Y, G-protein coupled, S NM_00S767 10161 0.096604616
AGI_HUMl_OUGO_A_23_P67228 SNAPC2 Small nuclear RNA activating complex, polypeptide 2, 45kDa NM_003083 6618 0.096604616
AGI_HUM1_OLIGO_A_23_P91076 FU 14681 Hypothetical protein FU14681 CR621710 84910 0.096604616
AG1_HUM1_OLIGO_A_24_P108242 GOSR2 Golgi SNAP receptor complex member 2 NM_004287 9570 0.096604616
AGI_HU 1_OLIGO_A_24_P168760 GTPBP1 GTP binding protein 1 NM_004286 9567 0.096604616
AGI_HUM1_OUGO_A_24_P347480 ENST000002386K 0.096604616
AGI_HUM1_OUGO_A_24_P912058 S76980 0.096604616
AGI_HUM1_OLIGO_A_32_P31633 SF3B1 Splicing factor 3b, subunit 1, 155kDa NM_012433 23451 0.096604616
AGI_HUM1_OUGO_A_23_P30474 FU 10233 Hypothetical protein FU 10233 NM_018034 55100 0.09712464
AGI_HUM1_OUGO_A_32_P178092 AFAP Hypothetical protein LOC254848 BC014113 60312 0.09745375
AGI_HUMl_OLIGO_A_23_P134714 HRSP12 Heat-responsive protein 12 NM_005836 10247 0.09762118
AGI_HU 1_OLIGO_A_32_P175098 ASPH Aspartate beta-hydroxylase CR613736 444 0.09762118
Core 1 UDP-galactose.N-acetylgalactosamine-alpha-R beta 1,3-
AGI_HUMl_OUGO_A_23_P252145 C1GALT1 galactosyltransferase NM_020156 56913 0.097940226
AGI_HUM1_OLIGO_A_23_P104692 MGC35521 Pellino 3 alpha NM_145065 246330 0.098033415
AGI_HUMl_OLIGO_A_23_P136238 MGC14327 Hypothetical protein MGC14327 NM_053045 94107 0.098033415
AGI_HUMl_OLIGO_A_23_P148879 ATP1A2 ATPase, Na+/K+ transporting, alpha 2 (+) polypeptide NM_000702 477 0.098033415
Table 1A - FDR for Change in Gene Expression Values Between Pre-and Post-Treatment Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_0UG0_A_23_P1S7147 ZDHHC4 Zinc finger, DHHC domain containing 4 NM_018106 55146 0.098033415
AGI_HUM1_0LIG0_A_23_P313512 DCP1B Decapping enzyme hDcplb NM_152640 196513 0.098033415
AGI_HUMl_OUGO_A_23_P336859 LOC284542 Hypothetical protein LOC284542 AK090467 284542 0.098033415
AGI_HUM1_OUGO_A_23_P383009 IGFBP5 Insulin-like growth factor binding protein 5 NM_000599 3488 0.098033415
AGI_HUM1_OUGO_A_23_P5051 GNA11 Guanine nucleotide binding protein (G protein), alpha 11 (Gq class) BC063426 2767 0.098033415
AGI_HUM l_OLIGO_A_24_P624 39 NM_001013672 0.098033415
AGI_HUMl_OLIGO_A_32_P125568 THC2416690 0.098033415
AGI_HU l_OUGO_A_32_P161681 NM_001008528 0.098033415
AGI_HUMl_OUGO_A_32_P184746 THC2378401 0.098033415
AGI_HU 1_OLIGO_A_32_P220127 RPL34 Ribosomal protein L34 NM_033625 6164 0.098033415
AGI_HUMl_OUGO_A_23_P114144 CXorf37 Chromosome X open reading frame 37 NM_014008 28952 0.09816416
AGI_HUMl_OUGO_A_23_P147185 CANX Calnexin NM_001746 821 0.09816416
AGI_HU l_OUGO_A_23_P213551 CSNK1A1 Casein kinase l, alpha l NM_001892 1452 0.09816416
AGI_HU 1_OUGO_A_24_P40165 PIGT Phosphatidylinositol glycan, class T NM_015937 51604 0.09816416
AGI_HU 1_OUGO_A_24_P621023 ENST000003738H 0.09816416
AGI_H UM 1_0U GO_A_32_ 10633 C22orf4 Chromosome 22 open reading frame 4 BC022417 25771 0.09816416
AGI_HUMl_OLIGO_A_23_P93722 SD 1 Sidekick homolog 1 (chicken) AK074077 221935 0.098210685
AGI_HUMl_OLIGO_A_23_P48835 KIF23 Kinesin family member 23 NM_138555 9493 0.098273168
AGI_HUM1_OUGO_A_23_P129301 ClSorf25 Chromosome 15 open reading frame 25 NM_018097 55142 0.098500774
AGI_HUMl_OUGO_A_23_P162739 TGFB1I4 Transforming growth factor beta 1 induced transcript 4 NM_183422 8848 0.098500774
AGI_HUMl_OUGO_A_32_P165713 CIP29 Cytokine induced protein 29 kDa NM_033082 84324 0.098500774
AGI_HUMl_OUGO_A_32_P2738 C10orf61 Chromosome 10 open reading frame 61 NM_015631 26123 0.098500774
AGI_HU l_OUGO_A_23_P155477 LOC51161 G20 protein NM_016210 51161 0.099065131
AGI_H UM l_OLI GO_A_23_P 164081 MYH10 Myosin, heavy polypeptide 10, non-muscle NM_005964 4628 0.099065131
AGI_HUMl_OUGO_A_23_P354591 NM_033446 0.099065131
AGI_HUM1_OUGO_A_23_P43484 CDKN2A Cyclin-dependent kinase inhibitor 2A (melanoma, pl6, inhibits CDK4) NM_058197 1029 0.099065131
AGI_HUMl_OLIGO_A_24_P195974 A_24_P195974 0.099131448
Caspase 2, apoptosis-related cysteine protease (neural precursor cell expressed,
AGI_HUMl_OUGO_A_24_P269398 CASP2 developmental^ down-regulated 2) NM_032982 835 0.099131448
AGI_HUMl_OUGO_A_32_P73775 KIAA0495 KIAA049S NM_207306 57212 0.099131448
AGI_HUMl_OUGO_A_32_P168561 THC2413666 0.099301528
AGI_HUM1_OUGO_A_23_P140301 PSMA3 Proteasome (prosome, macropain) subunit, alpha type, 3 NM_002788 5684 0.099409858
AGI_HUM1_OUGO_A_23_P140668 IDH3A Isocitrate dehydrogenase 3 (NAD+) alpha NM_005530 3419 0.099409858
AGI_HUMl_OLIGO_A_23_P163148 C14orfl33 Chromosome 14 open reading frame 133 NM_022067 63894 0.099409858
AGI_HUM1_OUGO_A_23_P219223 NM_080701 0.099409858
AGI_HUMl_OUGO_A_23_P23266 ENST0000036780i 0.099409858
AGI_HUM1_OUGO_A_23_P55045 SLC25A19 Solute carrier family 25 (mitochondrial deoxynucleotide carrier), member 19 . NM_021734 60386 0.099409858
AGI_HUMl_OLIGO_A_23_P87752 LEPREL2 Leprecan-like 2 NM_014262 10536 0.099409858
AGI_HUMl_OUGO_A_24_P175612 SFXN2 Sideroflexin 2 NM_178858 118980 0.099409858
AGI_HUM1_OUGO_A_23_P20864 ANGPTL2 Angiopoietin-like 2 NM_012098 23452 0.099636713
AGI_HUM1_OUGO_A_24_P220485 OLFML2A Olfactomedin-like 2A NM_182487 169611 0.099636713
AGI_HUMl_OLIGO_A_23_P125423 C1R Complement component 1, r subcomponent NM_001733 715 0.099983113
AGI_HUM1_0LIG0_A_23_P83493 CGI-90 CGI-90 protein NM_016033 51115 0.099983113
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_OUGO_A_23_P500410 ATP6V1G2 ATPase, H+ transporting, lysosomal 13kDa, VI subunit G isoform 2 NM_130463 534 0.00556686
AGI_HUM1_OUGO_A_23_P250313 KIAA1524 KIAA1524 protein AB040957 57650 0.00592933
AGI_HUMl_OUGO_A_23_P 18267 TUSC4 Tumor suppressor candidate 4 NM_006545 10641 0.00611253
AGI_HUMl_OUGO_A_24_P93741 LOC285398 Hypothetical protein LOC285398 AK098811 285398 0.00611253
AGI_HUMl_OUGO_A_23_P352684 WDR22 WD repeat domain 22 NM_003861 8816 0.00611253
AGI_HUM1_OLIGO_A_23_P329740 UBC Ubiquitin C NM_021009 7316 0.00884742
AGI_HUM1_0UG0_A_32_P65473 ENST00000330640 0.00884742
AGI_HU l_OLIGO_A_23_P57227 SNTA1 Syntrophin, alpha 1 (dystrophin-associated protein Al, 59kDa, acidic component) NM_003098 6640 0.00884742
AGI_HUM1_OUGO_A_23_P360964 GC15476 Thymus expressed gene 3-like NM_145056 147906 0.00961462
AGI_HUMl_OLIGO_A_23_P162466 PKP2 Plakophilin 2 NM_004572 5318 0.01072345
AGI_HUMl_OLIGO_A_24_P344961 AMOT Angiomotin NM_133265 154796 0.01072345
AGI_HUMl_OLIGO_A_24_P93462 A_24_P93462 0.01072345
AGI_HUMl_OUGO_A_24_P943613 TBC1D1 TBC1 (tre-2/USP6, BUB2, cdcl6) domain family, member 1 NMJ315173 23216 0.01072345
AGI_HUM1_OLIGO_A_23_P77310 SH3BP3 SH3-domain binding protein 3 NM_022473 64397 0.01072345
AGI_HUMl_OLIGO_A_23_P55926 NR1H2 Nuclear receptor subfamily 1, group H, member 2 NM_007121 7376 0.01072345
AGI_HUMl_OLIGO_A_23_P368484 FU35696 FU35696 protein NM_207387 388341 0.01072345
AGI_HUM1_OLIGO_A_24_P399680 C20orfl08 Chromosome 20 open reading frame 108 NM_080821 116151 0.01128431
AGI_HUM l_OUGO_A_23_P169738 SOX7 SRY (sex determining region Y)-box 7 NM_031439 83595 0.01216998
AGI_HUMl_OLIGO_A_24_P137434 DCBLD2 Discoidin, CUB and LCCL domain containing 2 NM_080927 131566 0.01216998
AGI_HUMl_OLIGO_A_23_P19134 MASS1 Monogenic, audiogenic seizure susceptibility 1 homolog (mouse) NM_032119 84059 0.01231733
AGI_HUM 1_OUGO_A_24_P200942 THG-1 TSC-22-like NM_030935 81628 0.01331317
AGI_HUM 1_OUGO_A_24_P337000 TTC7A Tetratricopeptide repeat domain 7A NM_020458 57217 0.01331317
AGI_HUM l_OLIGO_A_23_P333683 IGSF10 Immunoglobulin superfamily, member 10 NM_178822 285313 0.01454206
AGI_HUMl_OLIGO_A_24_P115621 ENST00000373218 0.01801736
AGI_HUMl_OUGO_A_23_P158885 LOCI 14977 Hypothetical protein BC014148 AK096342 114977 0.01836372
AGI_HUMl_OLIGO_A_24_P931944 CDNA FU25106 fis, clone CBR01467 AK 128814 0.01836372
AGI_HUMl_OUGO_A_23_P146654 BAG1 BCL2-associated athanogene NM_004323 573 0.01945735
AGI_HUMl_OLIGO_A_24_P378987 DHRSX Zinc finger, BED domain containing 1 NM_145177 207063 0.02031249
AGI_HUMl_OUGO_A_32_P135336 NR_002556 0.02031249
AGI_HUMl_OLIGO_A_32_P196837 DLK1 Delta-like 1 homolog (Drosophila) AA449494 8788 0.02031249
AGI_HUMl_OUGO_A_24_P314688 USP40 Ubiquitin specific protease 40 · NM_018218 55230 0.02031249
AGI_HU l_OLIGO_A_24_P289188 ENST00000287144 0.02066335
AGI_HUMl_OUGO_A_23_P24318 RPS6KB2 Ribosomal protein S6 kinase, 70kDa, polypeptide 2 NM_001007071 6199 0.0210813
AGI_HUM1_OUGO_A_23_P23630 CENTB5 Centaurin, beta S NM_030649 116983 0.0210813
AGI_HUMl_OLIGO_A_24_P287613 MAP2K1 Mitogen-activated protein kinase kinase 1 BC066984 5604 0.0210813
AGI_HUM1_0LIG0_A_23_P23194 PINK1 PTEN induced putative kinase 1 NM_032409 65018 0.0210813
AGI_HUM1_0LIG0_A_23_P94319 NM_014867 0.0210813
AGI_HUMl_OUGO_A_23_P151791 LTB4R Leukotriene B4 receptor NM_181657 1241 0.0210813
AGI_HUMl_OLIGO_A_23_P146354 PO T1 Protein-O-mannosyltransferase 1 NM_007171 10585 0.02121958
AGI_HUMl_OLIGO_A_23_P153461 LPPR2 Lipid phosphate phosphatase-related protein type 2 NM_022737 64748 0.02121958
AGI_HUM1_OUIGO_A_24_P820302 THC2411433 0.02121958
AGI_HUM1_OUGO_A_23_P308150 FU39827 Hypothetical protein FU39827 NM_152424 139285 0.02121958
AGI_HUMl_OUGO_A_24_P873764 BCR Breakpoint cluster region NM_004327 613 0.02121958
AGI_HUM1_OLIGO_A_24_P280903 ENST00000311218 0.02121958
AGI_HUMl_OLIGO_A_23_P395524 PWP1 Nuclear phosphoprotein similar to S. cerevisiae PWP1 NM_007062 11137 0.02121958
AGI_HU l_OLIGO_A_32_P175935 CDNA FU43172 fis, clone FCBBF3007242 AK125162 0.02121958
AGI_HUMl_OUGO_A_23_P62387 NUDT11 Nudix (nucleoside diphosphate linked moiety X)-type motif 11 NM_018159 55190 0.02121958
AGI_HUM1_OLIGO_A_23_P393080 CALML3 Calmodulin-like 3 NM_005185 810 0.02121958
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders o Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_OUGO_A_24_P418019 A_24_P418019 0.02121958 r-~ AGI_HUMl_OLIGO_A_23_P134693 NM_001009552 0.02121958 o AGI_HUM1_OLIGO_A_23_P207650 ACADVL Acyl-Coenzyme A dehydrogenase, very long chain NM_000018 37 0.02121958
AGI_HUM1_OLIGO_A_32_P116058 NR_002800 0.02121958
AGI_HU l_OLIGO_A_24_P737553 CDNA FU13712 fis, clone PLACE2000394 AK023774 0.02121958
AGI_HUMl_OUGO_A_32_P224586 THC2342537 0.02121958
AGI_HUM1_OUGO_A_23_P104295 SHFM3 Split hand/foot malformation (ectrodactyly) type 3 NM_022039 6468 0.02121958
AGI_HUM1_OUGO_A_32_P108592 THC2312637 0.02121958
AGI_HUM1_OLIGO_A_32_P100439 Ellsl Hypothetical protein Ellsl NM_152793 222166 0.02121958
AGI_HUM1_OL1GO_A_23_P218807 RoXaN Rotavirus X protein associated with NSP3 NM_017590 23264 0.02121958
AGI_HUM1_OUGO_A_23_P50799 OR10H2 Olfactory receptor, family 10, subfamily H, member 2 NM_013939 26538 0.02121958
AGI_HUM l_OLIGO_A_24_P98411 HSPA5 Heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa) NM_005347 3309 0.02121958
AGI_HUM1_OUGO_A_24_P380348 S AP1 Stromal membrane-associated protein 1 NM_021940 60682 0.02121958
AGI_HUM1_OLIGO_A_23_P356021 FANCB Fanconi anemia, complementation group B NM_152633 2187 0.02121958
AGI_HUM1_OUGO_A_32_P220798 CD34 CD34 antigen NM_001773 947 0.02121958
AGI_HUMl_OLIGO_A_24_P814444 THC2407545 0.02172937
AGI_HUM1_OUGO_A_23_P159650 C0X7B Cytochrome c oxidase subunit Vllb NM_001866 1349 0.02172937
AGI_HUMl_OLIGO_A_23_P97265 GPATC4 G patch domain containing 4 NM_182679 54865 0.02172937
AGI_HUM1_OUGO_A_24_P612020 SQST 1 Sequestosome 1 AK096241 8878 0.02172937
AGI_HUMl_OUGO_A_24_P73577 ALDH1A2 Aldehyde dehydrogenase 1 family, member A2 NM_170697 8854 0.02172937
AGI_HUM1_OUGO_A_24_P257201 MRPL30 Mitochondrial ribosomal protein L30 NM_145213 51263 0.02172937
AGI_HUMl_OUGO_A_23_P374284 CASC3 Cancer susceptibility candidate 3 NM_007359 22794 0.02172937
AGI_HUM1_OUGO_A_32_P142407 A_32_P142407 0.02172937
AGI_HUMl_OLIGO_A_24_P924957 RT18 Keratin 18 L32537 3875 0.02244126
AGI_HU 1_0UG0_A_23_P1S2199 CTRL Chymotrypsin-like NM_001907 1506 0.02244126
AGI_HUMl_OUGO_A_24_P67699 RPL23A Ribosomal protein L23a NM_000984 6147 0.02274152
AGI_HUMl_OUGO_A_23_P48585 SALL2 Sal-like 2 (Drosophila) NM_00S407 6297 0.02274152
AGI_HUM1_OUGO_A_24_P42330 LOC440523 AK090827 440523 0.02274152
Eukaryotic translation elongation factor 1 delta (guanine nucleotide exchange
AGI_HUMl_OUGO_A_23_P31833 EEF1D protein) NM_032378 1936 0.02301926
AGI_HU l_OUGO_A_24_P389415 NM_0072S7 0.02309658
AGI_HUM1_0UG0_A_23_P119794 Full-length cDNA clone CS0DM002YA18 of Fetal liver of Homo sapiens (human) CR608907 0.02333418
AGI_HU 1_OLIGO_A_23_P102420 CCT4 Chaperonin containing TCP1, subunit 4 (delta) NM_006430 10575 0.02343542
AGI_HUM l_OUGO_A_24_P29966 TRIM32 Tripartite motif-containing 32 NM_012210 22954 0.02352042
AGI_HUMl_OUGO_A_23_P66924 FU20071 Dymeclin NM_017653 54808 0.02352042
AGI_HUM1_OUGO_A_23_P139950 KPNA3 Karyopherin alpha 3 (importin alpha 4) NM_002267 3839 0.02352042
AGI_HUM1_OLIGO_A_23_P156708 TNXB Tenascin XB NM_019105 7148 0.02423024
AGI_HUM1_OUGO_A_24_P306558 KIAA1049 KIAA1049 protein NM_014972 22980 0.02423024
AGI_HU l_OLIGO_A_23_P89824 MGC11386 Hypothetical protein MGC11386 NM_032933 85019 0.02423447
AGI_HUMl_OLIGO_A_32_P23525 CDNA FU42287 fis, clone TLIVE2005866 A 124281 0.02423447
AGI_HUMl_OLIGO_A_24_P336577 LOC55924 Hypothetical protein LOC55924 NM_019099 55924 0.02423447
AGI_HUMl_OLIGO_A_23_P168847 FBX016 F-box protein 16 NM_172366 157574 0.02423447
AGI_HU 1_OUGO_A_24_P510377 Hypothetical gene supported by BC031250 BC031250 400751 0.02439724 o AGI_HU 1_OUGO_A_23_P202156 NFKB2 Nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (p49/pl00) NM_002502 4791 0.02439724
AGI_HUMl_OUGO_A_23_P57961 PLXNB1 Plexin Bl NM_002673 5364 0.02445234
AGI_HUM1_OUGO_A_23_P208310 ASE-l CD3-epsilon-associated protein; antisense to ERCC-1 NM_012099 10849 0.02445234
AGI_HUM1_OLIGO_A_23_P94660 TBC1D13 TBC1 domain family, member 13 NM_018201 54662 0.02445234
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_OUGO_A_24_P930796 C10orf72 Chromosome 10 open reading frame 72 AK001062 196740 0.02445234
AGI_HU 1_0UG0_A_32_P112881 ENST00000374274 0.02452672
AGI_HUMl_OUGO_A_24_P22892 KCTD15 Potassium channel tetramerisation domain containing 15 NM_024076 79047 0.02495697
AGI_HUM1_OLIGO_A_32_P117760 Transcribed locus BG208131 0.02495697
AGI_HUM1_OUGO_A_23_P59022 TRERF1 Transcriptional regulating factor 1 NM_033502 55809 0.02495697
AGI_HUMl_OUGO_A_23_P168449 RASA4 RAS p21 protein activator 4 NM_006989 10156 0.02495697
AGI_HUM1_OLIGO_A_23_P160159 SLC2A5 Solute carrier family 2 (facilitated glucose/fructose transporter), member 5 NM_003039 6518 0.02495697
AGI_HUMl_OUGO_A_23_P127793 FU35827 Hypothetical protein FU35827 NM_153265 256364 0.02495697
AGI_HUM1_OLIGO_A_23_P205228 ATP7B ATPase, Cu++ transporting, beta polypeptide (Wilson disease) NM_000053 540 0.02495697
AGI_HUM1_OUGO_A_24_P247820 AK074633 0.02505001
AGI_HUMl_OUGO_A_23_P351734 NPHP4 Nephronophthisis 4 NM_015102 261734 0.0259092
AGI_HUM1_OUGO_A_32_P109755 Unknown mRNA AF462446 0.02600757
AGI_HUM1_OUGO_A_32_P142700 C22orfl5 Chromosome 22 open reading frame 15 NM_182520 150248 0.02600757
AGI_HUMl_OUGO_A_23_P362183 SAMD6 Sterile alpha motif domain containing 6 NM_173551 203286 0.02600757
AGI_HUMl_OLIGO_A_24_P475556 LOC146346 Hypothetical protein LOC146346 AK057359 146346 0.02600757
AGI_HUMl_OLIGO_A_23_P258972 GOLGA1 Golgi autoantigen, golgin subfamily a, 1 NM_002077 2800 0.02600757
AGI_HUM1_OUGO_A_23_P2990 CEBPE CCAAT/enhancer binding protein (C/EBP), epsilon NM_001805 1053 0.02600757
AGl_HU l_OLIGO_A_24_P177964 KIAA1602 KIAA1602 protein BC033253 57701 0.02600757
Eukaryotic translation elongation factor 1 delta (guanine nucleotide exchange
AGI_HUM l_OLIGO_A_24_P821168 EEF1D protein) NM_032378 1936 0.02600757
AGI_HU 1_OUGO_A_23_P160523 TRIM45 Tripartite motif-containing 45 NM_025188 80263 0.02600757
AGI_HUMl_OLIGO_A_23_P135826 LOC114977 Hypothetical protein BC014148 AK096342 114977 0.02600757
AGI_HUM1_OUGO_A_24_P478940 A_24_P478940 0.02600757
AGI_HUM1_OUGO_A_32_P206989 CDNA FU13350 fis, clone OVARC1002143 AK023412 0.02600757
AGI_HUM1_OLIGO_A_32_P524014 ENST00000367545 0.02600757
AGI_HU l_OUGO_A_23_P11712S RARG Retinoic acid receptor, gamma NM_000966 5916 0.02600757
AGI_HUMl_OLIGO_A_23_P422144 FAM43A Family with sequence similarity 43, member A NM_153690 131583 0.02600757
AGI_HUMl_OUGO_A_24_P417935 CENTG1 Centaurin, gamma 1 CR590071 116986 0.02600757
AGI_HU l_OUGO_A_32_P75888 COMMD10 CO domain containing 10 CD243286 51397 0.02600757
AGI_HUM1_OUGO_A_24_P902653 MGC2747 Hypothetical protein MGC2747 CR616041 79086 0.02600757
AGI_HUMl_OUGO_A_23_P156284 DBN1 Drebrin 1 N _080881 1627 0.02600757
AGI_HUMl_OUGO_A_32_P224327 CDNA FU31839 fis, clone NT2RP7000086 AK056401 0.02600757
AGI_HUM1_OUGO_A_32_P144220 ENST00000374534 0.02600757
AGI_HU l_OUGO_A_32_P192 74 C6orf31 Chromosome 6 open reading frame 31 NM_030651 80863 0.02600757
AGI_HUM1_OUGO_A_24_P399630 PRKACA Protein kinase, cAMP-dependent, catalytic, alpha NM_002730 5566 0.02600757
AGI_HUM1_OLIGO_A_24_P203072 PHF16 PHD finger protein 16 · NM_014735 9767 0.02600757
AGI_HUM1_OLIGCLA_23_P50368 OSCAR Osteoclast-associated receptor NM_206818 126014 0.02600757
AGI_HU 1_OLIGO_A_23_P421401 PDGFRB Platelet-derived growth factor receptor, beta polypeptide NM_002609 5159 0.02600757
AGI_HUMl_OLIGO_A_23_P373598 MAFK V-maf musculoaponeurotic fibrosarcoma oncogene homolog K (avian) NM_002360 7975 0.02600757
AGI_HUM1_OUGO_A_23_P103084 TOM1 Target of mybl (chicken) NM_005488 10043 0.02600757
AGI_HUMl_OLIGO_A_23_P149427 CAPN9 Calpain 9 NM_006615 10753 0.02600779
AGI_HUMl_OUGO_A_23_P254863 GC42105 Hypothetical protein MGC42105 NM_153361 167359 0.02610687
AGI_HUM1_0L1G0_A_24_P344416 DSC3 Desmocollin 3 NM_024423 1825 0.02615967
AGI_HU l_OLIGO_A_23_P216282 ARHGEF10 Rho guanine nucleotide exchange factor (GEF) 10 NM_014629 9639 0.02626067
AGI_HUMl_OUGO_A_23_P14273 ZFYVE21 Zinc finger, FYVE domain containing 21 NM_024071 79038 0.02691455
AGI_HUMl_OLIGO_A_24_P713729 THC2373625 0.02706542
AGI_HUM1_OLIGO_A_23_P397055 CSGIcA-T Chondroitin sulfate glucuronyltransferase NM_019015 54480 0.02708649
AGI_HU 1_OUGO_A_24_P11045 THC2271174 0.02708649
AGI_HUMl_OLIGO_A_32_P171232 A_32_P171232 0.02708649
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUMl_OLIGO_A_23_P142125 HRC Histidine rich calcium binding protein NM_002152 3270 0.02708649
AGI_HUMl_OLIGO_A_23_P254165 RAI2 Retinoic acid induced 2 NM_021785 10742 0.02871497
AGI_HUM1_OLIGO_A_23_P208991 PALM Paralemmin NM_002579 5064 0.02871497
AGI_HUMl_OLIGO_A_24_P343289 CDC2L6 Cell division cycle 2-like 6 (CDK8-like) NM_015076 23097 0.02871497
AGI_HUM1_0LIG0_A_23_P114105 LDOC1 < Leucine zipper, down-regulated in cancer 1 NM_012317 23641 0.02934208
AGI_HUM1_OLIGO_A_32_P460399 MRNA full length insert cDNA clone EUROIMAGE 2362292 AL365520 0.02949116
AGI_HUM1_OL1GO_A_23_P4604 ZNF600 Zinc finger protein 600 NM_198457 162966 0.02977394
AGI_HUMl_OUGO_A_23_P253723 RRH Retinal pigment epithelium-derived rhodopsin homolog NM_006583 10692 0.02977394
AGI_HUMl_OLIGO_A_24_P84279 EBPL Emopamil binding protein-like NM_032565 84650 0.03082569
AGI_HUM1_OLIGO_A_23_P502371 PHF2 PHD finger protein 2 NM_024517 5253 0.03120828
AGI_HUMl_OLIGO_A_32_P84342 THC2315140 0.03192985
AGI_HUMl_OUGO_A_23_P155477 LOC51161 G20 protein NM_016210 51161 0.03192985
AGI_HU 1_OLIGO_A_24_P923704 TOLUP Toll interacting protein AF321778 54472 0.03192985
AGI_HUM1_OLIGO_A_23_P80048 NR_001442 0.03192985
AGI_HUMl_OLIGO_A_23_P154338 EFHD1 EF hand domain containing 1 NM_025202 80303 0.03192985
AGI_HUM1_OLIGO_A_23_P408996 OACTl O-acyltransferase (membrane bound) domain containing 1 AK131269 154141 0.03192985
AGI_HUM1_0LIG0_A_23_P211141 DSCAM Down syndrome cell adhesion molecule ' NM_001389 1826 0.03192985
AGI_HUMl_OUGO_A_32_P16315 ENST00000272035 0.03192985
AGI_HUMl_OLIGO_A_24_P289818 ENST00000370659 0.03192985
AGI_HUMl_OLIGO_A_23_P375165 FU35767 FU35767 protein NM_207459 400629 0.03192985
AGI_HUM1_OLIGO_A_32_P45780 THC2282384 0.03192985
AGI_HUMl_OLIGO_A_24_P921823 ENST00000369397 0.03192985
AGI_HUMl_OUGO_A_23_P144458 CAMK2D Calcium/calmodulin-dependent protein kinase (CaM kinase) II delta NM_001221 817 0.03192985
AGI_HUMl_OUGO_A_23_P687S9 TFF1 Trefoil factor 1 (breast cancer, estrogen-inducible sequence expressed in) NM_003225 7031 0.03192985
AGI_HUMl_OLIGO_A_32_P221799 HIST1H2AM Histone 1, H2am NM_003514 8336 0.03192985
AGI_HUM1_0LIG0_A_32_P110433 THC2273687 0.03192985
AGI_HUMl_OLIGO_A_23_P16S778 MLPH Melanophilin NM_024101 79083 0.03192985
AGI_HUMl_OLIGO_A_32_P156851 DSCR1L1 Down syndrome critical region gene l-like 1 NM_00S822 10231 0.03192985
AGI_HUMl_OLIGO_A_23_P315933 WBSCR21 Williams Beuren syndrome chromosome region 21 NM_031295 83451 0.03192985
AGI_HU l_OLIGO_A_24_P64344 BLNK B-cell linker NM_013314 29760 0.03192985
AGI_HUM1_OL1GO_A_23_P32903 OCRL Oculocerebrorenal syndrome of Lowe NM_000276 4952 0.03192985
Protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting
AGI_HUM1_OLIGO_A_23_P320553 PPFIA3 protein (liprin), alpha 3 NM_003660 8541 0.0321749
AGI_HUM1_OLIGO_A_32_P55106 THC2374814 0.0321749
AGI_HUMl_OLIGO_A_24_P263543 ENST00000277860 0.03231425
AGI_HUMl_OLIGO_A_23_P65674 TMOD3 Tropomodulin 3 (ubiquitous) NM_014547 29766 0.03231425
AGI_HUM1_OLIGO_A_23_P257609 RPL29 Ribosomal protein L29 NM_000992 6159 0.03231425
AGI_HUMl_OLIGO_A_24_P276864 FU20297 Hypothetical protein FU20297 NM_017951 55627 0.0327972
AGI_HUM1_0L1G0_A_24_P118341 KENAE Kenae BF869497 202243 0.03286109
AGI_HUM1_0LIG0_A_23_P431268 PLEKHA6 Pleckstrin homology domain containing, family A member 6 NM_014935 22874 0.03286109
AGI_HUM1_OLIGO_A_24_P367804 BC024651 0.03286109
AGI_HUMl_OUGO_A_23_P24433 CTSF Cathepsin F NM_003793 8722 0.03286109
AGI_HUMl_OLIGO_A_32_P96692 THC2340838 0.03286109
AGI_HUM1_OLIGO_A_23_P48570 DHRS2 Dehydrogenase/reductase (SDR family) member 2 NM_182908 10202 0.03286109
AGI_HUM1_OLIGO_A_24_P302898 BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) NM_004656 8314 0.03286109
AGI_HUMl_OLIGO_A_23_P96369 FU10178 Hypothetical protein FU10178 NM_018015 55086 0.03286109
AGI_HUMl_OLIGO_A_24_P322444 NUP62 Nucleoporin 62kDa NM_153719 23636 0.03286109
AGI_H U M l_OLIGO JA_24_P936692 Homo sapiens, clone IMAGE :4822684, mRNA BC033528 0.03286109
AGI_HUM 1_OLIGO_A_23_P164011 SOX IS SRY (sex determining region Y)-box 15 NM_006942 6665 0.03286109
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders o Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUMl_OUGO_A_24_P289383 CHD7 Chromodomain helicase DNA binding protein 7 NM_017780 55636 0.03300997
O r~ AGI_HU 1_OUGO_A_24_P160874 DUT DUTP pyrophosphatase NM_001948 1854 0.03307712 o AGI_HUMl_OUGO_A_24_P788227 LOC440156 BC041856 440156 0.03307712
AGI_HUM l_OUGO_A_23_P338919 AK055387 0.03307712
AGI_HUM1_OUGO_A_24_P302374 CLCN6' Chloride channel 6 NM_001286 1185 0.03307712
AGI_HUMl_OUGO_A_32_P222362 DRG1 Developmental^ regulated GTP binding protein 1 AK127132 4733 0.03326542
AGI_HUMl_OUGO_A_23_P85585 LCN7 Lipocalin 7 NM_022164 64129 0.03326542
AGl_HUMl_OUGO_A_24_P185986 MGC23937 Hypothetical protein MGC23937 similar to CG4798 NM_145052 139596 0.03340835
AGI_HUMl_OLIGO_A_32_P27327 ITM1 Integral membrane protein 1 W27166 3703 0.03340835
AGI_HUM1_OUGO_A_23_P2530S2 CD99L2 CD99 antigen-like 2 NM_031462 83692 0.03377243
AGI_HU 1_OLIGO_A_24_P409471 ENST00000316861 0.03449789
AGI_HUMl_OLIGO_A_24_P275873 TBCD Tubulin-specific chaperone d NM_005993 6904 0.03459929
AGI_HUM1_OLIGO_A_23_P356004 CSEN Calsenilin, presenilin binding protein, EF hand transcription factor NM_013434 30818 0.03471589
AGI_HUMl_OLIGO_A_24_P226248 ZMAT2 Zinc finger, matrin type 2 NM_144723 153527 0.03471589
AGI_HUMl_OLIGO_A_24_P374652 NUC S Nuclear ubiquitous casein kinase and cyclin-dependent kinase substrate NM_022731 64710 0.03471589
AGI_HUM1_OLIGO_A_23_P104224 ACF Apobec-1 complementation factor NM_138933 29974 0.03471589
AGI_HUM1_OLIGO_A_24_P270769 VPS35 Vacuolar protein sorting 35 (yeast) N _018206 55737 0.03471589
AGIJHU l_OUGO_A_23_P89113 FU14154 Hypothetical protein FU14154 NM_024845 79903 0.03471589
AGI_HUMl_OLIGO_A_24_P942112 P0LR1B Polymerase (RNA) I polypeptide B, 128kDa NM_019014 84172 0.0348849
AGI_HUMl_OUGO_A_23_P111452 CENTG3 Centaurin, gamma 3 NM_031946 116988 0.03501603
AGI_HUMl_OLIGO_A_23_P72127 KIAA1446 Brain-enriched guanylate kinase-associated protein NM_020836 57596 0.03519474
AGI_HUM1_OLIGO_A_32_P176018 LOC81569 Actin like protein NM_030812 81569 0.03532587
AGI_HU M l_OUGO_A_32_P319200 GGTL4 Gamma-glutamyltransferase-like 4 NM_199127 91227 0.03544083
AGI_HUMl_OUGO_A_24_P97849 DBN1 Drebrin 1 NM_080881 1627 0.03544083
AGI_HUM1_OUGO_A_24_P75708 A_24_P75708 0.03544083
AGI_HUMl_OLIGO_A_32_P82293 A_32_P82293 0.03544083
AGI_HUMl_OUGO_A_24_P358279 A_24_P358279 0.03544083
AGI_HUMl_OUGO_A_23_P79587 ALPP Alkaline phosphatase, placental (Regan isozyme) NM_001632 250 0.03544083
AGI_HUMl_OUGO_A_24_P283928 MGC2731 Hypothetical protein MGC2731 NM_024068 79035 0.03544083
AGI_HUM1_OUGO_A_24_P101271 A_24_P101271 0.03546775
AGI_HUMl_OUGO_A_32_P226186 THC2266474 0.03546775
AGI_HUM1_OUGO_A_23_P88580 ARID3B AT rich interactive domain 3B (BRIGHT- like) NM_006465 10620 0.03562191
AGI_HUMl_OUGO_A_23_P146855 C22orfl Chromosome 22 open reading frame 1 NM_001585 758 0.03562191
AGI_HUMl_OUGO_A_23_P115743 C10orf84 Chromosome 10 open reading frame 84 NM_022063 63877 0.03579344
AGI_HUM1_OLIGO_A_23_P408768 D0T1L DOTl-like, histone H3 methyltransferase (S. cerevisiae) NM_032482 84444 0.03579344
AGI_HUMl_OLIGO_A_24_P58331 FU22955 Hypothetical protein FU22955 NM_024819 79877 0.03579344
AGI_HUM1_OUGO_A_32_P101623 THC2337763 0.03579344
AGI_HUM l_OUGO_A_23_P141680 BCAS3 Breast carcinoma amplified sequence 3 NM_017679 54828 0.03579344
CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) small
AGI_HUM1_OUGO_A_23_P81880 CTDSP2 phosphatase 2 NM_005730 10106 0.03579344
90 AGI_HUM1_OUGO_A_32_P26017 DB380193 0.03579344 90 AGI_HUMl_OUGO_A_23_P26713 RPL23 Ribosomal protein L23 NM_000978 9349 0.03579344
AGI_HUMl_OUGO_A_23_P123256 PDAP1 PDGFA associated protein 1 N _014891 11333 0.03579344
AGI_HUMl_OUGO_A_24_P125311 A_24_P125311 0.03579344
O AGI_HUM1_OUGO_A_23_P104252 IT1H5 Inter-alpha (globulin) inhibitor H5 NM_030569 80760 0.03579344 o AGI_HUMl_OLIGO_A_32_P134657 IAA0240 KIAA0240 NM_015349 23506 0.03579344
AGI_HUMl_OLIGO_A_24_P113295 AP2S1 Adaptor-related protein complex 2, Sigma 1 subunit NM_004069 1175 0.03579344
AGI_HUMl_OUGO_A_23_P17811 SEC14L2 SEC14-like 2 (S. cerevisiae) NM_012429 23541 0.03579344
AGI_HUM1_OUGO_A_23_P13057 PRDM11 PR domain containing 11 NM_020229 56981 0.03579344
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_OLIGO_A_23_P70827 KIAA1549 KIAA1549 protein AL136736 57670 0.03579344
AG I_H U l_OLI GO_A_23_P84118 CDH18 Cadherin 18, type 2 NM_004934 1016 0.03581628
AGI_HUMl_OUGO_A_32_P32653 SENP5 SUMOl/sentrin specific protease 5 BC036626 205564 0.03588595
AGI_HUMl_OUGO_A_32_P183765 ERBB4 V-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) AK126298 2066 0.03588595
AGI_HUM1_OUGO_A_23_P35820 CFL1 Cofilin 1 (non-muscle) NM_005507 1072 0.03588595
AGI_HUMl_OUGO_A_24_P941268 CA5B Inactivation escape 2 NM_007220 11238 0.03588595
AGI_HUMl_OUGO_A_23_P57199 GGTLA4 Gamma-glutamyltransferase-like activity 4 NM_080920 92086 0.03588595
AGI_HU 1_OLIGO_A_23_P101532 RPS11 Ribosomal protein Sll NM_001015 6205 0.03590805
AGI_HUMl_OUGO_A_23_P143981 FBLN2 Fibulin 2 NM_001004019 2199 0.03619918
AGI_HUM1_OLIGO_A_24_P68008 ENST00000294485 0.03668376
AGI_HUMl_OUGO_A_32_P177477 THC2344152 0.03673976
AGI_HUM1_OUGO_A_23_P117380 C14orfl52 Chromosome 14 open reading frame 152 NM_138344 90050 0.0369129
AGI_HUM1_OLIGO_A_23_P421011 KAZALD1 Kazal-type serine protease inhibitor domain 1 NM_030929 81621 0.0370985
AGI_HUM1_OLIGO_A_23_P80759 PVRL3 Poliovirus receptor-related 3 BC017572 25945 0.0370985
AGI_HUMl_OLIGO_A_23_P18292 RPL14 Ribosomal protein L14 NM_003973 9045 0.03825962
AGI_HUM1_OLIGO_A_24_P108779 FU12242 Hypothetical protein FU12242 NM_024681 79734 0.03825962
AGI_HUMl_OUGO_A_24_P753592 BCO 18589 0.03825962
AGI_HUM1_OUGO_A_23_P250164 HGD Homogentisate 1,2-dioxygenase (homogentisate oxidase) NM_000187 3081 0.03825962
AGI_HUMl_OUGO_A_23_P154849 OLIG1 Oligodendrocyte transcription factor 1 NM_138983 116448 0.03825962
AGI_HUMl_OUGO_A_24_P296568 CBX1 Chromobox homolog 1 (HP1 beta homolog Drosophila ) NM_006807 10951 0.03825962
AGI_HUM1_OUGO_A_23_P315106 ENST00000380410 0.03892307
AGI_HUMl_OUGO_A_32_P38637 KIAA1862 KIAA1862 protein NM_032534 84626 0.03892307
AGI_HUMl_OUGO_A_23_P22382 D FZP434P1750 DKFZP434P1750 protein NM_015527 26000 0.03956369
AGI_HUMl_OUGO_A_32_P194563 THC2281660 0.03973329
Splicing factor, arginine/serine-rich 16 (suppressor-of-white-apricot homolog,
AGI_HUMl_OLIGO_A_23_P78517 SFRS16 Drosophila) NM_007056 11129 0.03973329
AGI_HUMl_OUGO_A_23_P168868 PTDSS1 Phosphatidylserine synthase 1 NM_014754 9791 0.03973329
AGI_HUM1_OUGO_A_24_P7330 A_24_P7330 0.03973329
AGI_HUM1_OUGO_A_23_P316850 C19orfl9 Chromosome 19 open reading frame 19 NM_182577 284451 0.03973329
AGI_HUMl_OUGO_A_23_P428992 ENST00000382579 0.03973329
AGI_HUMl_OUGO_A_23_P69141 DNCLI1 Dynein, cytoplasmic, light intermediate polypeptide 1 NM_016141 51143 0.03973329
AGI_HU l_OUGO_A_23_P112429 RPL35 Ribosomal protein L35 NM_007209 11224 0.03973329
AGI_HU 1_OUGO_A_23_P18082 FU14566 Hypothetical protein FU14566 NM_032806 84892 0.03977095
AGI_HUMl_OLIGO_A_23_P27424 ZNF418 Zinc finger protein 418 NM_133460 147686 0.03977095
AGI_HUM1_OLIGO_A_24_P392082 ENST00000361800 0.03977095
AGI_HUM1_OUGO_A_32_P104023 THC2346121 0.03977095
AGI_HUMl_OUGO_A_23_P159974 LHL13 Kelch-like 13 (Drosophila) NM_033495 90293 0.03978727
AGI_HUMl_OLIGO_A_24_P659113 FU40432 Hypothetical protein FU40432 NM_152523 151195 0.03998933
AGI_HUM1_OUGO_A_23_P203819 GOLGA3 Golgi autoantigen, golgin subfamily a, 3 NM_005895 2802 0.04003625
AGI_HUMl_OUGO_A_32_P234996 THC2311218 0.04003625
AGI_HUMl_OUGO_A_23_P149375 CTMP C-terminal modulator protein NM_053055 117145 0.04003625
AGI_HU 1_OLIGO_A_23_P404059 PASD1 PAS domain containing 1 N _173493 139135 0.04003625
AGI_HUM1_OUGO_A_23_P201368 CTBS Chitobiase, di-N-acetyl- N _004388 1486 0.04008632
AGI_HUMl_OUGO_A_23_P117298 F7 Coagulation factor VII (serum prothrombin conversion accelerator) N _000131 2155 0.04008632
AGI_HUM1_OUGO_A_32_P49350 CR609307 0.040121
AGIJHUM l_OUGO_A_32_P26443 THC2258710 0.040121
AGI_HUM l_OLIGO_A_24_P384119 XM_942451 0.04032726
AGI_HUMl_OUGO_A_23_P147388 KIF13B Kinesin family member 13B NM_015254 23303 0.04032726
AGI_HUMl_OUGO_A_23_P393697 MGC27345 Hypothetical protein GC27345 BC024231 157247 0.0405513
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_OUGO_A_24_P290263 A_24_P290263 0.04072885
AGI_HUMl_OUGO_A_23_P168556 STX1A Syntaxin 1A (brain) NM_004603 6804 0.04072885
AGI_HUM1_OLIGO_A_23_P218108 WDFY2 WD repeat and FYVE domain containing 2 NM_052950 115825 0.04114115
AGI_HUMl_OUGO_A_24_P278853 FU14624 Hypothetical protein FU14624 NM_032813 84899 0.04114115
AGI_HUM1_OLIGO_A_23_P161041 LHL12 Kelch-like 12 (Drosophila) N _021633 59349 0.04114115
AGI_HUMl_OLIGO_A_32_P214758 THC2383313 0.04114115
AGI_HU l_OUGO_A_23_P6398 AP1B1 Adaptor-related protein complex 1, beta 1 subunit NM_001127 162 0.04114115
AGI_HUM1_OUGO_A_24_P40928 ENST00000281228 0.04285574
AGI_HUM1_OUGO_A_24_P3804 NM_001039651 0.04285574
AGI_HUM 1_OLIGO_A_24_P403403 RPL35 Ribosomal protein L35 NM_007209 11224 0.04285574
AGI_HUMl_OLIGO_A_23_P16866 VIL1 Villin 1 NM_007127 7429 0.0429901
AGI_HU 1_OUGO_A_23_P202672 RNH Ribonuclease/angiogenin inhibitor NM_002939 6050 0.04300262
AGI_HUM1_OLIGO_A_24_P30314 SCYL1 SCYl-like 1 (S. cerevisiae) NM_020680 57410 0.04341005
AGI_HU l_OUGO_A_23_P168928 CYP11B1 Cytochrome P450, family 11, subfamily B, polypeptide 1 NM_000497 1584 0.04343043
AGI_HUMl_OUGO_A_24_P567298 CSAG2 CSAG family, member 2 NM_004909 9598 0.04350798
AGI_HUMl_OUGO_A_32_P164593 FU13842 Hypothetical protein FU 13842 N _024645 79698 0.04353467
AGI_HUMl_OLIGO_A_32_P118532 CDNA clone IMAGE:5288145, partial cds CR625518 0.0436705
AGI_HUM1_OLIGO_A_23_P45304 X Kell blood group precursor (McLeod phenotype) NM_021083 7504 0.04373896
AGI_HUM1_OLIGO_A_23_P155360 HDAC11 Histone deacetylase 11 NM_024827 79885 0.04377807
AGI_HUM1_OUGO_A_32_P107833 THC2404842 0.04377807
AGI_HUM1_OUGO_A_23_P76059 ENST00000354743 0.04382447
AGI_HUM1_OUGO_A_23_P50399 NM_138353 0.04382447
Caspase 2, apoptosis-related cysteine protease (neural precursor cell expressed,
AGI_HU l_OUGO_A_24_P269398 CASP2 developmentally down-regulated 2) NM_032982 835 0.04426263
AGI_HUM1_OLIGO_A_23_P96990 NVL Nuclear VCP-like NM_002533 4931 0.04449602
AGI_HUMl_OUGO_A_23_P142671 ZNF513 Zinc finger protein 513 NM_144631 130557 0.04484926
AGI_HUMl_OLIGO_A_32_P192922 LOC157562 Hypothetical protein LOC157562 AL050061 157562 0.04506291
AGI_HUMl_OLIGO_A_24_P333357 RAB40C RAB40C, member RAS oncogene family AK090463 57799 0.04506291
AGI_HUM1_OUGO_A_23_P210619 C20orf43 Chromosome 20 open reading frame 43 NM_016407 51507 0.04506291
AGI_HUMl_OUGO_A_23_P143559 CLTCL1 Clathrin, heavy polypeptide-like 1 NM_007098 8218 0.04506291
AGI_HUM1_OUGO_A_32_P134209 THC2403913 0.04506291
AGI_HUM1_OLIGO_A_23_P205370 ASB2 Ankyrin repeat and SOCS box-containing 2 NM_016150 51676 0.04509918
AGI_HUMl_OLIGO_A_23_P67299 DOC 6 Dedicator of cytokinesis 6 N _020812 57572 0.04509918
AGI_HUMl_OLIGO_A_23_P153651 FSD1 Fibronectin type 3 and SPRY domain containing 1 NM_024333 79187 0.04509918
AGI_HUMl_OLIGO_A_23_P22744 PAGE-5 PAGE-S protein NM_130467 90737 0.04509918
AGI_HUM1_OUGO_A_23_P208158 DTNA Dystrobrevin, alpha NM_001392 1837 0.04509918
AGI_HUMl_OLIGO_A_32_P133926 A_32_P133926 0.04509918
AGI_HUMl_OLIGO_A_24_P298946 A_24_P298946 0.04542651
AGI_HUM1_OUGO_A_32_P19840 Hypothetical LOC402617 CK300181 402617 0.04542651
AGI_HUMl_OLIGO_A_23_P389897 NGFR Nerve growth factor receptor (TNFR superfamily, member 16) NM_002507 4804 0.04574742
AGI_HUM1_OUGO_A_24_P383440 IAA0033 KIAA0033 protein BC035034 23027 0.04673016
AGI_HUM 1_OLIGO_A_32_P42780 THC2338292 0.04673016
AGI_HUM1_OUGO_A_23_P206454 MGC16385 Hypothetical protein MGC16385 NM_145039 92806 0.04673016
AGI_HUMl_OUGO_A_24_P332971 RPL7L1 Ribosomal protein L7-like 1 NM_198486 285855 0.04673016
AGI_HUMl_OUGO_A_24_P576445 A 098124 0.04676639
AGI_HUM1_OLIGO_A_24_P125096 MT1X Metallothionein IX NM_005952 4501 0.04676639
AG I_H UM l_OU GO_A_23_P 118135 THC2308359 0.04676639
AGI_HUMl_OLIGO_A_23_P16615 HNRPM Heterogeneous nuclear ribonucleoprotein M NM_005968 4670 0.04676639
AGI_HUMl_OLIGO_A_24_P416961 ARVCF Armadillo repeat gene deletes in velocardiofacial syndrome NM_001670 421 0.04676639
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUM1_OLIGO_A_23_P107432 FU35934 FU35934 protein NM_207453 400579 0.04676639
AGI_HUM1_OUGO_A_24_P270424 DPF3 D4, zinc and double PHD fingers, family 3 AK124946 8110 0.04676639
AGI_HUM1_OLIGO_A_23_P12603 RNF153 Ring finger protein 153 NM_017824 54708 0.04676639
AGI_HUMl_OLIGO_A_23_P333218 NM_001031711 0.04676639
AGI_HUMl_OUGO_A_32_P47616 AW994273 0.04681701
AGI_HUMl_OUGO_A_23_P7144 CXCL1 Chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha) NM_001511 2919 0.04688504
AGI_HUM1_OUGO_A_23_P500244 TRPV1 Transient receptor potential cation channel, subfamily V, member 1 NM_080706 7442 0.04688504
AGI_HUM1_OLIGO_A_23_P96302 SPANXA2 SPANX family, member.A2 NM_013453 64650 0.04688504
AGI_HUM1_OLIGO_A_23_P350005 FU25801 Hypothetical protein FU25801 NM_173553 205860 0.04688504
AGI_HUM1_OUGO_A_23_P309739 ESR1 Estrogen receptor 1 NM_000125 2099 0.04688504
AGI_HUMl_OUGO_A_24_P945283 DLG3 Discs, large homolog 3 (neuroendocrine-dlg, Drosophila) AB033058 1741 0.04688504
AGI_HUMl_OUGO_A_23_P218237 LCAT Lecithin-cholesterol acyltransferase NM_000229 3931 0.04688504
AGI_HUM1_OLIGO_A_23_P19036 TNIP1 TNFAIP3 interacting protein 1 NM_006058 10318 0.04688504
AGI_HUM1_OUGO_A_23_P409168 KIAA0540 KIAA0540 protein AK131104 23218 0.04688504
AG I_HU M l_OU GO_A_23_P 141946 LTBP4 Latent transforming growth factor beta binding protein 4 NM_003573 8425 0.0472703
AGI_HUM1_OUGO_A_23_P40400S MGC29729 Hypothetical protein MGC29729 NM_152274 92002 0.0472703
AGI_HUM1_OLIGO_A_32_P99690 ENST00000380985 0.0472703
AGI_HUMl_OUGO_A_32_P46313 CF529502 0.04754191
AGI_HUM1_OUGO_A_24_P7085 NR_002778 0.04774837
AGI_HUM1_OUGO_A_32_P220591 THC2415124 0.04774837
AGI_HUMl_OUGO_A_24_P931845 HCG8 HLA complex group 8 AY358246 80869 0.04815713
AGI_HUM1_OLIGO_A_23_P500892 TUB Tubby homolog (mouse) NM_003320 7275 0.04823615
AGI_HUM1_OUGO_A_23_P24960 FU23441 Hypothetical protein FU23441 NM_024678 79731 0.04823615
AGI_HUMl_OLIGO_A_23_P133596 RNASE3L Nuclear RNase III Drosha NM_013235 29102 0.04823615
AGI_HUM1_OLIGO_A_23_P201672 KIAA0859 KIAA0859 NM_015935 51603 0.04823615
AGI_HUMl_OUGO_A_24_P562242 A_24_P562242 0.04866814
AGI_HUMl_OUGO_A_32_P132276 BE091362 0.04869837
AGI_HUMl_OLIGO_A_32_P212654 BU616488 0.04869837
AGI_HUMl_OLIGO_A_24_P525749 Homo sapiens, clone IMAGE:4214962, mRNA AK091547 0.04872217
AGI_HUM1_OUGO_A_23_P503182 ABR Active BCR-related gene NM_021962 29 0.04875589
AGI_HUM1_OUGO_A_32_P155026 ENST00000371189 0.04875589
AGI_HUMl_OLIGO_A_23_P167256 PHF17 PHD finger protein 17 AK127326 79960 0.04894323
AGI_HU l_OUGO_A_24_P392958 C20orfl40 Chromosome 20 open reading frame 140 BX647370 128637 0.04894323
AGI_HU l_OLIGO_A_32_P96752 SOX4 SRY (sex determining region Y)-box 4 AW946823 6659 0.04894323
AGI_HUMl_OUGO_A_23_P21S832 ATP5J2 ATP synthase, H+ transporting, mitochondrial FO complex, subunit f, isoform 2 NM_004889 9551 0.04894323
AGI_HUM 1_0L1G0_A_32_P1587 ACYP2 Acylphosphatase 2, muscle type BQ066852 98 0.04894323
AGI_HUMl_OLIGO_A_24_P99216 LR 10 Low density lipoprotein receptor-related protein 10 N _014045 26020 0.04894323
AGI_HUMl_OUGO_A_23_P72627 HGS Hepatocyte growth factor-regulated tyrosine kinase substrate NM_004712 9146 0.04897374
AGI_HUMl_OUGO_A_32_P132827 ENST00000355520 0.04902203
AGI_HUMl_OUGO_A_32_P192692 NM_001014797 0.04902203
AGI_HUM1_OUGO_A_23_P68059 NSPC1 Likely ortholog of mouse nervous system polycomb 1 NM_032673 84759 0.04902203
AGI_HUM1_OUGO_A_23_P130731 TBC1D17 TBC1 domain family, member 17 NM_024682 79735 0.04902203
AGI_HUMl_OUGO_A_23_P217178 AGEC1 Melanoma antigen, family C, 1 NM_005462 9947 0.04902203
AGI_HU 1_OLIGO_A_23_P204511 FU20489 Hypothetical protein FU20489 NM_017842 55652 0.04902203
AGI_HU 1_OUGO_A_23_P85140 TCEAL2 Transcription elongation factor A (Sll)-like 2 NM_080390 140597 0.04902203
AGI_HUMl_OUGO_A_24_P136691 MGC11257 Hypothetical protein MGC11257 BC025971 84310 0.04902203
AGI_HUMl_OLIGO_A_32_P182186 BC041955 0.04902203
Table 2 - FDR for Comparison of Baseline Arm and Back Samples Between Responders and Non-Responders
Agilent Probe ID Gene Symbol Gene Name Accession Entrez Gene ID FDR
AGI_HUMl_OLIGO_A_32_P81674 LOC157627 Hypothetical protein LOC157627 AK091593 157627 0.04902203
AGI_HUMl_OLIGO_A_23_P 167537 CPLX2 Complexin 2 NM_006650 10814 0.04902203
AGI_HUM1_OUGO_A_23_P202881 FEZ1 Fasciculation and elongation protein zeta 1 (zygin I) NM_005103 9638 0.04902203
AGI_HUMl_OLIGO_A_24_P412486 Similar to RIKEN cDNA 8030451K01 CR601315 387921 0.04902203
AGI_HU l_OLIGO_A_32_P77742 THC2338229 0.04902203
AGI_HUM l_OLIGO_A_23_P74887 SDC3 Syndecan 3 (N-syndecan) AB007937 9672 0.04902203
AGI_HUM l_OLIGO_A_23_P95764 PRPS1 Phosphoribosyl pyrophosphate synthetase 1 NM_002764 5631 0.04902203
AGI_HUM1_OLIGO_A_23_P107166 ACBD4 Acyl-Coenzyme A binding domain containing 4 NM_024722 79777 0.04915923
AGI_HUMl_OUGO_A_23_P42435 DTNBP1 Dystrobrevin binding protein 1 NM_183041 84062 0.04925664
AGI_HUMl_OUGO_A_32_P194915 THC2449703 0.04965406
AGI_HU 1_OLIGO_A_32_P154079 TGFB1I4 Transforming growth factor beta 1 induced transcript 4 AL533377 8848 0.0499513
AGI_HUMl_OUGO_A_24_P47467 MGC5508 Hypothetical protein MGC5508 N _024092 79073 0.0499513

Claims

WHAT IS CLAIMED IS:
1. A method of determining if a patient having Systemic Sclerosis (SSc) or scleroderma is a responder to mycophenolate mofetil (MMF) treatment or a non-responder to MMF treatment, comprising (a) comparing a gene expression signature obtained from skin of a patient having SSc or scleroderma to a gene expression signature that is characteristic of a responder to MMF treatment and (b) based on results of comparing in (a), determining if the patient is a responder or a non-responder to MMF treatment.
2. The method of claim 1, wherein the gene expression signature is obtained from skin that is a skin sample obtained from the arm of the patient or from the back of the patient.
3. The method of claim 1, wherein in (a), the gene expression signature obtained from skin of the patient is compared with a gene expression signature characteristic of a responder to MMF treatment that comprises altered expression of one or more genes in Group III, altered expression of one or more genes in Group II, altered expression of one or more genes in Group I or a combination thereof and comparing shows that the gene expression signature obtained from skin of the patient comprises altered expression of one or more genes in Group III, altered expression of one or more genes in Group II, altered expression of one or more genes in Group III or any combination of the three and the patient having SSc is determined to be a responder to MMF treatment.
4. The method of claim 2, wherein:
(a) Group III comprises: genes identified by name: A2M, AIF1, ALOX5AP, APOL2, APOL3, BATF, BCL3, BIRCl, BTN3A2, ClOorflO, Clorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTL1, CP A3, CPVL, CTAG1B, DDX58, EBI2, EVI2B, F13A1, FAM20A, FAP, FCGR3A, FLJ11259, FLJ22573, FLJ23221, FLJ25200, FYB, GBP1, GBP3, GEM, GIMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLS1, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB 1 , HLA-DRB5, ICAM2, IFI16, IFI16, IFIT1, IFIT2, IFITM1, IFITM2, IFITM3, IL10RA, INDO, ITGB2, KIAA0063, LAMB1, LCP1, LGALS2, LGALS9, LILRB2, LOC387763, LOC400759, LUM, LYZ, MARCKS, MFNG, MGC24133, MPEGl, MRCl, MRCL3, MS4A6A, MXl, NNMT, NUP62, PAG, PLAU, PPIC, PPIC, PTPRC, RAC2, RGS10, RGS16, RSAFD1, SAT, SCGB2A1, SLC20A1, SLC02B1, SPARC, SULF1, TAP1, TCTEL1, TIMP1, TNFSF4, UBD, VSIG4, and ZFYVE26 and genes, each identified by GenBank accession number: AF533936, BQ049338, ENST00000310210, ENST00000313904, ENST00000329660, 1 1000437, 1 966691, M15073, NM 001010919, NM 001025201, NM 001033569, THC1543691, and XM 291496 and the altered expression is increased expression;
(b) Group II comprises genes, identified by name: AADAC, ADAM17, ADH1A, ADH1C, AHNAK, ALG1, ALG5, AMOT, AOX1, AP2A2, ARK5, ARL6IP5,
ARMCX1, BECN1, BECN1, BMP8A, BNIP3L, C10orfl l9, Clorf24, Clor07,
C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6, CCNG2, CDC26, CDK2AP1, CDR1, CFHL1, CNTN3, CPNE5, CRTAP, CTNNA1, CTSC, CUTL1, CXCL5, CYBRD1, CYP2R1, DBN1, DCAMKL1, DCL-1, DIAPH2, DKK2, ECHDC3, ECM2, EIF3S7, EMB, EMCN, EMILIN2, ENPP2, EPB41L2, FBLNl, FBLN2, FEMIA, FGL2, FHL5, FKBP7, FLU, FLJ10986, FLJ20032, FLJ20701, FLJ23861, FLJ34969, FLJ36748, FLJ36888, FLJ43339, FZR1, GABPB2, GARNL4, GHITM, GHR, GIT2, GLYAT, GPM6B, GTPBP5, HELB, HOXB4, IFNA6, IGFBP5, IL13RA1, IL15, KAZALD1, KCNK4, KCNS3, KCTD10, KIAA0232,
KIAA0494, KIAA0562, KIAA0870, KIAA1190, KIF25, KLHL18, KLK2, LAMP2, LEPROTL1, LHFP, LM02, LOCI 14990, LOC255458, LOC387680, LOC400027, LOC493869, LOC87769, LRBA, MAFB, MAGEH1, MAN2B2, MCCC2, MEGF10, MFAP5, MGC11308, MGC15523, MGC3200, MGC35048, MGC45780, MOGAT3, MPPE1, MPZ, MYOIB, MYOC, NFYC, NIPSNAP3B, OPTN, OSR2, PAM, PBXIP1, PCOLCE2, PDGFC, PDGFRA, PDGFRL, PEX19, PHAX, PIP, PKM2, PKP2, PMP22, POU2F1, PPAP2B, PRAC, PSMA5, PSORS1C1, PTGIS, RECK, RGS11, RGS5, RIMS3, RIPK2, RNASE4, RNF125, RNF13, RNF146, RNF19, ROBOl, ROB03, RPL7A, SARA1, SAV1, SCGB1D1, SDK1, SECP43, SECTM1, SERPINB2, SGCA, SH3BGRL, SH3GLB1, SH3RF2, SLC10A3, SLC12A2, SLC14A1, SLC39A14,
SLC7A7, SLC9A9, SLPI, SMAD1, SMAP1, SMARCE1, SMP1, SNTG2, SNX7, SOCS5, SSPN, STX7, SUMF1, TAS2R10, TDE2, TFAP2B, TGFBR2, THSD2,
TM4SF3, TMEM25, TMEM34, TNA, TNKS2, TRAD, TRAF3IP1, TREM4, TRIM35, TRIM9, TTYH2, TUBB1, UBL3, ULK2, URB, USP54, UST, UTRN, UTX, WIF1, WWOX, XG, YPEL5, and ZFHX1B and genes, each identified by GenBank accession number only: A_32_BS 169243, A_32_BS200773, A_32_BS53976, AC025463,
AF124368, AF161364, AF318337, AF372624, AK001565, AK022793, AK055621, AK056856, AL050042, AL137761, BC035102, BC038761, BC039664, BG252130, BI014689, D80006, ENST00000298643, ENST00000300068, ENST00000305402, ENST00000307901, ENST00000321656, ENST00000322803, ENST00000329246, ENST00000331640, ENST00000332271, ENST00000333784, H16080, 1 1861543, 1 1882608, 1 1985061, 1_3335767, 1 3551568, 1 3588329, 1 932413, 1_962800, 1 966091, NM 001008528, NM 001009555, NM 001013632, NM 001014975, NM_001018006, NM_001018076, NM_001025077, NM_003671, NM_014758,
NM_015262, NM_138411, NM_153030, NMJ73709, NM_213595, NR_002184, S62210, THC1419743, THC1429821, THC1457118, THC1459712, THC1461073, THC1506312, THC1511927, THC1515028, THC1525318, THC1531579, THC1544941, THC1551463, THC1559236, THC1560798, THC1563147, THC1572906, THC1574967, THC1591470, XM 165930, and XM 209429 and altered expression is increased expression; and
(c) Group I comprises genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C12orfl4, C14orfl31, CACNG6, CBLL1 , CBX8, CDC7, CDT1, CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1, FGF5, FLJ10902, FLJ12438, FLJ12443, FLJ12484, FLJ12572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS3, IKBKG, IL23A, INSIG1, KIAA1509, KIAA1609, KIAA1666, LDLR, LGALS8, LILRB5, LOC123876, LOC128977, LOC153561, LOC283464, LRRIQ2, LY6K, MAC30, ME2, MGC13186, MGC16044, MGC16075, MGC29784, MGC33839, MGC35212, MGC4293, MICB, MLL5, MTRFIL, MUC20, NICNl, NPTXl, OAS3, OGDHL, OPRKl, PCNT2, PDZKl, PlTPNCl, PPFIA4, PREB, PRKY, PSMDl 1, PSPH, PSPHL, PTP4A3, PXMP2, RAB15, RAD51AP1, RIP, RNF121, RPL41, RPS18, RPS4Y1, RPS4Y2, S100P, SORD, SP1, SYMPK, SYT6, TM9SF4, TMOD3, TNFRSF12A, TPRA40, TRIP, TRPM7, TTR, TUBB4, VARS2L, ZNF572, and ZSCAN2 and genes, each identified by GenBank accession number: A 24 BS934268, AB065507, AC007051 , AI791206, AK022745, AK022893, AK022997, AK094044, AL391244, AL731541, AL928970, BC010544,
BC020847, BM925639, BM928667, ENST00000328708, ENST00000333517,
1 1891291, 1 3580313, NM_001009569, NM_001024808, NMJ72020, NMJ73705,
NMJ78467, NR_001544, THC1434038, THC1484458, THC1504780, U62539,
XM_210579, XM_303638, and XM_371684 and altered expression is decreased expression.
The method of claim 1 , wherein the gene expression signature that is characteristic of a responder to MMF treatment comprises: genes, each identified by name: A2M, AIF1, ALOX5AP, APOL2, APOL3, BATF, BCL3, BIRCl, BTN3A2, ClOorflO, Clorf38,
C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTL1, CP A3, CPVL,
CTAGIB, DDX58, EBI2, EVI2B, F13A1, FAM20A, FAP, FCGR3A, FLJ11259, FLJ22573, FLJ23221, FLJ25200, FYB, GBP1, GBP3, GEM, GIMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLSl, HLA-DMA, HLA-DOA, HLA-DPAl, HLA-DPBl, HLA-DQAl, HLA- DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB5, ICAM2, IFI16, IFIT1, IFIT2, IFITM1, IFITM2, IFITM3, IL10RA, INDO, ITGB2, KIAA0063, LAMB1, LCP1, LGALS2,
LGALS9, LILRB2, LOC387763, LOC400759, LUM, LYZ, MARCKS, MFNG, MGC24133, MPEG1, MRC1, MRCL3, MS4A6A, MX1, NNMT, NUP62, PAG, PLAU, PPIC, PTPRC, RAC2, RGS10, RGS16, RSAFD1, SAT, SCGB2A1, SLC20A1, SLC02B1, SPARC, SULF1, TAP1, TCTEL1, TIMP1, TNFSF4, UBD, VSIG4, and ZFYVE26 and genes, each identified by GenBank accession number: AF533936, BQ049338, ENST00000310210, ENST00000313904, ENST00000329660, 1 1000437, 1 966691, M15073, NM 001010919, NM 001025201, ΝΜ ΟΟ 1033569, THC1543691, and XM 291496 and the altered expression is increased expression.
The method of claim 1, wherein in (a), the gene expression signature obtained from skin of the patient is compared with a gene expression signature characteristic of a non-responder to MMF treatment.
A method of determining if a patient having Systemic Sclerosis (SSc) or scleroderma is a responder to mycophenolate mofetil (MMF) treatment or a non-responder to MMF treatment, comprising (a) comparing a gene expression signature obtained from skin of a patient having SSc or scleroderma to a gene expression signature standard that is characteristic of a responder to MMF treatment and (b) based on results of comparing in (a), determining if the patient is a responder or a non-responder to MMF treatment, wherein the gene expression signature of a responder to MMF treatment comprises one or more genes listed in Table 1 , Table 1A, Table 2, Table 3, Table 4, Table 5 or Figure 1, and wherein the difference in expression of the one or more genes between the patient and the standard is statistically significant.
8. A method of determining if a patient having Systemic Sclerosis (SSc) or scleroderma is a responder to mycophenolate mofetil (MMF) treatment or a non-responder to MMF treatment, comprising:
(a) measuring expression of one or more genes selected from the group consisting of:
A2M, AIF1, ALOX5AP, APOL2, APOL3, BATF, BCL3, BIRCl , BTN3A2, ClOorflO, Clorf38, C6orf80, CCL2, CCL4, CCR5, CD8A, CDW52, COL6A3, COTL1, CP A3, CPVL, CTAG1B, DDX58, EBI2, EVI2B, F13A1, FAM20A, FAP, FCGR3A,
FLJ11259, FLJ22573, FLJ23221, FLJ25200, FYB, GBP1, GBP3, GEM, GIMAP6, GMFG, GZMH, GZMK, HAVCR2, HCLS1, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB5, ICAM2, IFI16, IFIT1, IFIT2, IFITM1, IFITM2, IFITM3, IL10RA, INDO, ITGB2, KIAA0063, LAMB1, LCP1, LGALS2, LGALS9, LILRB2, LOC387763, LOC400759, LUM, LYZ, MARCKS, MFNG, MGC24133, MPEG1, MRC1, MRCL3, MS4A6A, MX1, NMT, NUP62, PAG, PLAU, PPIC, PTPRC, RAC2, RGS10, RGS16, RSAFD1, SAT, SCGB2A1, SLC20A1, SLC02B1, SPARC, SULF1, TAP1, TCTEL1, TIMP1, TNFSF4, UBD, VSIG4, and ZFYVE26 and genes, each identified by GenBank accession number: AF533936, BQ049338, ENST00000310210, ENST00000313904, ENST00000329660, 1 1000437, 1 966691, M15073, NM 001010919, NM 001025201, NM 001033569, THC1543691 and XM 291496 in a skin sample obtained from a patient having Systemic Sclerosis (SSc) or scleroderma; and
(b) comparing expression of the one or more genes measured in (a) with expression of the corresponding one or more genes in a standard, wherein if expression of the one or more genes measured in (a) is increased relative to the standard, the patient is a responder to MMF treatment and if expression of the one or more genes measured in (a) is not increased relative to the standard, the patient is a non-responder to MMF treatment.
9. The method of claim 8, wherein measuring in (a) comprises obtaining nucleic acids from the skin sample; hybridizing nucleic acids obtained with a microarray comprising nucleic acid capable of hybridizing with at least one of the one or more of the genes in (a); and determining if hybridization occurs, wherein if hybridization occurs, at least one of the one or more genes is present in the skin sample.
10. The method of claim 8, further comprising:
(c) measuring expression of one or more genes selected from the group consisting of: genes, identified by name: A AD AC, ADAM 17, ADH1A, ADH1C, AHNAK, ALG1, ALG5, AMOT, AOX1, AP2A2, ARK5, ARL6IP5, ARMCX1, BECN1, BECN1, BMP8A, BNIP3L, C10orfl l9, Clorf24, Clor07, C20orfl0, C20orf22, C5orfl4, C6orf64, C9orf61, CAPS, CASP4, CASP5, CAST, CAV2, CCDC6, CCNG2, CDC26, CDK2AP1, CDR1, CFHL1, CNTN3, CPNE5, CRTAP, CTNNA1, CTSC, CUTL1, CXCL5, CYBRD1, CYP2R1, DBN1, DCAMKL1, DCL-1, DIAPH2, DKK2, ECHDC3, ECM2, EIF3S7, EMB, EMCN, EMILIN2, ENPP2, EPB41L2, FBLN1, FBLN2, FEM1A, FGL2, FHL5, FKBP7, FLU, FLJ10986, FLJ20032, FLJ20701, FLJ23861, FLJ34969, FLJ36748, FLJ36888, FLJ43339, FZR1, GABPB2, GARNL4, GHITM, GHR, GIT2, GLYAT, GPM6B, GTPBP5, HELB, HOXB4, IFNA6, IGFBP5, IL13RA1, IL15, KAZALD1, KCNK4, KCNS3, KCTD10, KIAA0232, KIAA0494, KIAA0562, KIAA0870, KIAA1190, KIF25, KLHL18, KLK2, LAMP2, LEPROTLl, LHFP, LM02, LOCI 14990, LOC255458, LOC387680, LOC400027, LOC493869, LOC87769, LRBA, MAFB, MAGEH1, MAN2B2, MCCC2, MEGF10, MFAP5, MGC11308, MGC15523, MGC3200, MGC35048, MGC45780, MOGAT3, MPPE1, MPZ, MYOIB, MYOC, NFYC, NIPSNAP3B, OPTN, OSR2, PAM, PBXIP1, PCOLCE2, PDGFC, PDGFRA, PDGFRL, PEX19, PHAX, PIP, PKM2, PKP2, PMP22, POU2F1 , PPAP2B, PRAC, PSMA5, PSORS1C1, PTGIS, RECK, RGS11, RGS5, RIMS3, RIPK2, RNASE4, RNF125, RNF13, RNF146, RNF19, ROBOl, ROB03, RPL7A, SARA1, SAV1, SCGB1D1, SDK1, SECP43, SECTM1, SERPINB2, SGCA, SH3BGRL, SH3GLB1, SH3RF2, SLC10A3, SLC12A2, SLC14A1, SLC39A14, SLC7A7, SLC9A9, SLPI, SMADl, SMAPl, SMARCEl, SMPl, SNTG2, SNX7, SOCS5, SSPN, STX7, SUMFl, TAS2R10, TDE2, TFAP2B, TGFBR2, THSD2, TM4SF3, TMEM25, TMEM34, TNA, TNKS2, TRAD, TRAF3IP1, TREM4, TRIM35, TRIM9, TTYH2, TUBB1, UBL3, ULK2, URB, USP54, UST, UTRN, UTX, WIF1, WWOX, XG, YPEL5, and ZFHX1B and genes, each identified by GenBank accession number only: A 32 BS 169243, A_32_BS200773, A_32_BS53976, AC025463, AF124368, AF161364, AF318337, AF372624, AK001565, AK022793, AK055621, AK056856, AL050042, AL137761, BC035102, BC038761, BC039664, BG252130, BI014689, D80006,
ENST00000298643, ENST00000300068, ENST00000305402, ENST00000307901, ENST00000321656, ENST00000322803, ENST00000329246, ENST00000331640, ENST00000332271, ENST00000333784, H16080, 1 1861543, 1 1882608, 1 1985061, I_3335767, 1 3551568, 1 3588329, 1 932413, 1_962800, 1 966091, NM_001008528, NM 001009555, NM 001013632, NM 001014975, NM 001018006, NM 001018076, NM_001025077, NM_003671, NM_014758, NM_015262, NM_138411, NM_153030, NMJ73709, NM_213595, NR_002184, S62210, THC1419743, THC1429821, THC1457118, THC1459712, THC1461073, THC1506312, THC1511927,
THC1515028, THC1525318, THC1531579, THC1544941, THC1551463,
THC1559236, THC1560798, THC1563147, THC1572906, THC1574967,
THC1591470, XM 165930, and XM 209429;
(d) measuring the expression of at least one or more genes selected from the group consisting of: genes, each identified by name: ANP32A, APOH, ATAD2, B3GALT6, B3GAT3, C12orfl4, C14orfl31, CACNG6, CBLL1, CBX8, CDC7, CDT1, CENPE, CGI-90, CLDN6, CREB3L3, CROC4, DDX3Y, DERP6, DJ971N18.2, EHD2, ESPL1, FGF5, FLJ10902, FLJ12438, FLJ12443, FLJ12484, FLJ12572, FLJ20245, FLJ32009, FLJ35757, FXYD2, GABRA2, GATA2, GK, GSG2, HPS3, IKBKG, IL23A, INSIG1, KIAA1509, KIAA1609, KIAA1666, LDLR, LGALS8, LILRB5, LOC123876,
LOC128977, LOC153561, LOC283464, LRRIQ2, LY6K, MAC30, ME2, MGC13186, MGC16044, MGC16075, MGC29784, MGC33839, MGC35212, MGC4293, MICB, MLL5, MTRFIL, MUC20, NICNl, NPTXl, OAS3, OGDHL, OPRKl, PCNT2, PDZKl, PITPNC1, PPFIA4, PREB, PRKY, PSMD11, PSPH, PSPHL, PTP4A3, PXMP2, RAB15, RAD51AP1, RIP, RNF121, RPL41, RPS18, RPS4Y1, RPS4Y2, S100P, SORD, SP1, SYMPK, SYT6, TM9SF4, TMOD3, TNFRSF12A, TPRA40, TRIP, TRPM7, TTR, TUBB4, VARS2L, ZNF572, and ZSCAN2 and genes, each identified by GenBank accession number: A 24 BS934268, AB065507, AC007051, ΑΓ791206, AK022745, AK022893, AK022997, AK094044, AL391244, AL731541, AL928970, BC010544, BC020847, BM925639, BM928667, ENST00000328708, ENST00000333517,
1 1891291, 1 3580313, NM_001009569, NM_001024808, NMJ72020, NMJ73705, NMJ78467, NR_001544, THC1434038, THC1484458, THC1504780, U62539, XM_210579, XM_303638, and XM_371684; and
(e) comparing expression of the one or more genes measured in (c) with expression of the corresponding one or more genes in a standard and expression of the one or more genes measured in (d) with expression of the corresponding one or more genes in a standard, wherein if expression of the one or more genes measured in (c) is increased relative to the standard and expression of the one or more genes measured in (d) is decreased relative to the standard, the patient is a responder to MMF treatment.
11. The method of claim 10, wherein measuring in (c) and in (d) comprises obtaining nucleic acids from the skin sample; hybridizing nucleic acids obtained with a microarray comprising nucleic acid capable of hybridizing with at least one of the one or more of the genes in (c) and/or (d); and determining if hybridization occurs, wherein if hybridization occurs, at least one of the one or more genes is present in the skin sample.
12. A microarray comprising nucleic acids that hybridize to at least one gene selected from
Group III or to a complement of at least one gene selected from Group III, a gene selected from Group II or to a complement thereof, and a gene selected from Group I or to a complement thereof.
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