WO2008067065A2 - Procédés, kits et systèmes pour diagnostiquer et pronostiquer le cancer de la prostate en utilisant des biomarqueurs sécrétés - Google Patents

Procédés, kits et systèmes pour diagnostiquer et pronostiquer le cancer de la prostate en utilisant des biomarqueurs sécrétés Download PDF

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WO2008067065A2
WO2008067065A2 PCT/US2007/081792 US2007081792W WO2008067065A2 WO 2008067065 A2 WO2008067065 A2 WO 2008067065A2 US 2007081792 W US2007081792 W US 2007081792W WO 2008067065 A2 WO2008067065 A2 WO 2008067065A2
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optionally
another embodiment
spock
ltf
secretory proteins
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WO2008067065A3 (fr
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Shiv Srivastava
Albert Dobi
Kee-Hong Kim
Gyorgy Petrovics
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Shiv Srivastava
Albert Dobi
Kee-Hong Kim
Gyorgy Petrovics
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate

Definitions

  • the present invention relates to secreted protein biomarkers for prostate cancer, diagnostic and prognostic kits comprising reagents that bind the secreted protein biomarkers, and methods and systems employing those biomarkers to diagnose and prognose prostate cancer.
  • Prostate cancer is the most common malignancy in American men and the third leading cause of cancer mortality.
  • PSA serum prostate specific antigen
  • PSA can lead to early detection of prostate cancer, it does not permit the clinician to differentiate between indolent prostate cancer and clinically significant disease.
  • prostate cancer In its early stages, prostate cancer is usually sensitive to androgen therapy, but patients almost uniformly relapse as androgen-independent tumor cells emerge. Further, approximately 30-40% of patients treated with radical prostatectomy for localized prostate cancer have microscopic disease that is not organ-confined and a significant portion of these patients relapse. (Singh et al., (2000) Cancer Cell 1 :203-09; Henshell et at., (2003) Cancer Res.
  • the present application provides secreted protein biomarkers for prostate cancer, methods and systems for using those biomarkers to diagnose and prognose prostate cancer, and diagnostic and prognostic kits comprising reagents that bind the secreted protein biomarkers.
  • one of the disclosed biomarkers is measured or detected in a diagnostic assay to determine whether prostate tumor cells are present in a sample.
  • the biomarkers comprise a panel of two or more different secreted proteins, and these proteins are measured or detected in a diagnostic assay to determine whether prostate tumor cells are present in a sample.
  • a diagnostic kit can be used to detect or measure the biomarkers.
  • the diagnostic kits can be used to measure the levels of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or more secreted proteins.
  • the diagnostic assay detects or measures the levels of one or more of the secreted proteins NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and PM 5.
  • the assay further comprises detecting or measuring PSA, %fPSA, PSA doubling time, PSA velocity, prostate volume, or a combination of these indicators.
  • the present application also provides prognostic kits that detect or measure the levels of one or more secreted proteins in a sample.
  • the prognostic kits are used in methods of predicting prostate cancer progression or severity, such as whether the prostate cancer is a moderate risk prostate cancer or a high risk prostate cancer, or to predict whether the prostate cancer is progressing, regressing, or in remission.
  • the prognostic kits can also be used to predict disease-free survival following radical prostatectomy.
  • one prognostic secreted protein is detected.
  • the prognostic panel comprises two or more different secreted proteins. Accordingly, assays using the prognostic kits can detect or measure the levels of one or more secreted proteins.
  • a prognostic kit can be used to measure the levels of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or more secreted proteins.
  • the prognostic assay detects or measures the levels of one or more of the secreted proteins SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164.
  • the assay further comprises detecting or measuring PSA, %fPSA, PSA doubling time, PSA velocity, prostate volume or a combination of these indicators.
  • an increase in the levels of the secreted protein(s) indicates the presence of prostate tumor cells. In other diagnostic embodiments, it is a decrease in expression levels of the secreted protein(s) that indicates the presence of prostate tumor cells. In still other diagnostic embodiments, the expression level of one or more of the secreted protein(s) is increased, while the expression level of one or more other secreted protein(s) is decreased. In yet other diagnostic embodiments, the relevant parameter is whether one or more proteins in the secreted protein panel is detectable or undetectable.
  • an increase in the levels of the secreted protein(s) is used to predict a moderate or a high risk prostate cancer.
  • a decrease in expression levels of the secreted protein(s) is used to predict a moderate or a high risk prostate cancer.
  • the expression level of one or more of the secreted protein(s) is increased, while the expression level of one or more other secreted protein(s) is decreased.
  • the relevant parameter is whether a secreted protein is detectable or undetectable.
  • the method of diagnosing or prognosing prostate cancer can comprise:
  • the altered expression of the one or more secreted proteins in the patient sample relative to the control indicates the presence of prostate cancer.
  • the altered expression of the one or more secreted proteins in the patient sample relative to the control is predictive of disease severity, for example a moderate risk prostate cancer or a high risk prostate cancer, or is predictive of whether the prostate cancer is progressing, regressing, or in remission.
  • increases and decreases of at least 10% relative to a control can be used in the diagnostic and prognostic methods, other values may also be used.
  • the increase or decrease may be at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or even 500%.
  • the increase or decrease may also be expressed in terms of statistical significance, where a statistically significant increase or decrease in expression, such as p ⁇ 0.05, p ⁇ 0.01 , p ⁇ 0.005, or p ⁇ 0.001 , indicates the presence of prostate cancer or a higher predisposition to develop prostate cancer, prostate cancer progression, or disease severity.
  • the disclosure also provides computer systems comprising artificial neural network (ANN) models that have been trained with prostate cancer diagnostic or prognostic data.
  • the ANN is a diagnostic ANN. Accordingly, it has been trained with data obtained from detecting or measuring one or more of the secreted proteins NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and PM 5.
  • the ANN has been trained with data obtained from detecting or measuring one or more of the secreted proteins SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164.
  • the ANN models are used to prognose prostate cancer. Both diagnostic and prognostic ANN models can also be trained with additional clinical data, including but not limited to prostate volume, PSA values, %fPSA, PSA doubling time, PSA velocity, digital rectal exam results, patient ethnicity, and patient age.
  • the biological sample tested in either the diagnostic or prognostic assays can be tissue, including prostate tissue, or a biofluid.
  • biofluids include serum, plasma, whole blood, urine (including post digital rectal exam ("post- DRE") urine), saliva, and prostatic fluid.
  • the diagnostic and prognostic kits comprise, for each secreted protein to be detected or measured, a reagent that detects or measures the secreted protein.
  • the reagent can be an antibody, including an antibody that is, optionally, detectably labeled and that binds to the secreted protein.
  • the reagent is a binding protein other than an antibody. Examples of binding proteins include soluble forms of natural receptors for the biomarkers.
  • Binding proteins can also be detectably labeled, if desired.
  • the antibodies and binding proteins can be used in soluble form, or they can be attached to a solid support, such as a bead, chip, or plate.
  • the kit comprises one or more antibodies and one or more binding proteins.
  • the secreted protein is an enzyme, it can be detected or measured by detecting or measuring its effect on a substrate.
  • a kit may comprise a substrate in combination with one or more antibodies, one or more binding proteins, or a combination of antibodies and binding proteins.
  • the secreted proteins in the biological sample can be detected or measured using techniques known in the art, such as enzyme-linked immunosorbant assays (ELISA), protein arrays, or colorimetric assays.
  • ELISA enzyme-linked immunosorbant assays
  • protein arrays protein arrays
  • colorimetric assays colorimetric assays
  • Figure 1 compares the expression levels of certain genes selected as diagnostic markers.
  • the data show normalized expression units for each gene in two databases: the CPDR database and the Oncomine database.
  • Figure 2 compares protein expression levels of selected diagnostic markers in pooled serum of patients with prostate cancer (CaP) and with metastatic disease (Met).
  • Figure 3 compares protein expression levels of two biomarkers and evaluates the sensitivity of those biomarkers.
  • Expression levels of SPOCK1 (Fig. 3A) and PLA2G7 (Fig. 3B) are presented for a cohort of patients with prostate cancer (CaP) and for controls.
  • a linear classifer algorithm Support Vector Machine (“SVM")
  • ANN artificial neural network
  • FIG 3E presents protein expression levels of SPOCK in individual control (CTL) and prostate cancer (CaP) samples in the top panel, while the bottom panel provides a comparison between the two sets of data.
  • Figure 5 presents protein expression levels of CRISP3 in individual control (CTL) and prostate cancer (CaP) samples in the top panel, while the bottom panel provides a comparison between the two sets of data.
  • Figure 6 presents protein expression levels of SMOC1 (Fig. 6A) and F5 (Fig. 6B) in urine samples as compared to serum PSA levels (Fig. 6C).
  • Figure 7 correlates the probability of prostate cancer as a function of the number of up-regulated genes analyzed.
  • Figure 8 shows that the probability of prostate cancer diagnosis increases as expression data for increasing numbers of genes encoding secreted proteins is combined.
  • Figure 9 illustrates the training of an artificial neural network (ANN) using gene expression data from TMEFF2, NPY, CRISP3, SMOC2, PLA2G7, SPOCK, and F5.
  • the upper left panel presents the normalization histogram of data distribution for the level of each biomarker
  • the upper right panel plots various transfer functions for the best classifiers of an ANN model
  • the lower panel presents the performance of the ANN tested and validated by the gene expression data.
  • altered protein expression refers both to qualitative differences (i.e., that a protein is detectable versus undetectable) and to quantitative differences (i.e., differences in measured levels of a protein).
  • NPY neuropeptide Y (tyrosine). It is encoded, for example, by NCBI Entrez GenelD: 4852.
  • An example of the amino acid sequence of preproNPY is published in the NCBI database under the accession number NP_000896, and is: MLGNKRLGLS GLTLALSLLV CLGALAEAYP KPDNPGEDA PAEDMARYYS ALRHYINLIT RQRYGKRSSP ETLISDLLMR ESTENVPRTR LEDPAMW
  • SPOCK is sparc/osteonectin, cwcv and kazal-like domains proteoglycan 1. It is encoded, for example, by NCBI Entrez GenelD NOS: 6695 (SPOCK1 ), 9806 (SPOCK2), and 50859 (SPOCK3).
  • SPOCK1 is published in the NCBI database under the accession number NP_004589, and is:
  • Amino acids 1-21 of SEQ ID NO: 2 correspond to a signal peptide.
  • the mature form of SPOCK1 corresponds to amino acids 22-439 of SEQ ID NO: 2.
  • SPOCK2 corresponds to amino acids 1-424 of SEQ ID NO: 3.
  • SPOCK3 (SEQ ID NO: 4) .
  • the mature form of SPOCK3 corresponds to amino acids 1-433 of SEQ ID NO: 4.
  • the mature form of isoform2 of SPOCK3 corresponds to amino acids 1- 436 of SEQ ID NO: 5.
  • SPOCK refers to SPOCK1 , SPOCK2, and SPOCK3. SPOCK is also known as testican, SPARC, and osteonectin. It has been associated with prostate cancer metastasis to the bone. (Thomas et al., (2000) CLIN. CANCER RES. 6; 1140-49; de et al., (2003) J. BIOL. CHEM. 278(40): 39044-50.) Antibody-based assays have also shown that it is present at elevated levels in the serum of melanoma patients. (Ikuta et al., (2005) CLIN. CANCER RES. 11 : 8079-88.)
  • CRISP3 cysteine-rich secretory protein 3. It is encoded, for example, by NCBI Entrez GenelD: 10321. An example of the amino acid sequence is published in the NCBI database under the accession number NP_006052 and is:
  • CRISP3 is also known as SGP28. Its mRNA is overexpressed in prostate cancer. (Kosari et al., (2002) CANCER EPIDEMIOL. BIOMARKERS & PREV. 11 : 1419-26.) Both glycosylated and non- glycosylated forms of CRISP3 exist, and ELISA and immunoblotting have been used to detect CRISP3 in human plasma and seminal plasma. (Udby et al., (2002) J. IMMUNOL. METH. 263: 43-55.)
  • PKA2G7 is phospholipase A2, group VII. It is encoded, for example, by NCBI Entrez GenelD: 7941. An example of the amino acid sequence is published in the NCBI database under the accession number NP_005075, and is:
  • PLA2G7 is also known as platelet-activating factor acetylhydrolase. Monoclonal antibodies to PLA2G7 have been produced (e.g., Rodrigo et al. (2001 ) BIOCHEM. J. 354: 1-7), but the protein can also be detected in biofluids such as seminal plasma by measuring enzymatic digestion of a substrate (e.g., Zhu et al., (2006) FERTILITY & STERILITY 85: 391-94).
  • TEFF2 is transmembrane protein with EGF-like and two follistatin- like domains 2. It is encoded, for example, by NCBI Entrez GenelD: 23671. An example of the amino acid sequence is published in the NCBI database under the accession number NP_057276, and is:
  • YSSDNTTRAS TRLI (SEQ ID NO: 8) .
  • TMEFF2 is also known as tomoregulin. It is an androgen-regulated transmembrane protein whose expression decreases as tumor cells acquire androgen-independence. (Gery et al. (2002) ONCOGENE 21 : 4739-46; Chen et al., (2006) CANCER LETTERS 244:274-88.) TMEFF2 has been used as a target in immunotherapy of prostate cancer with monoclonal antibodies conjugated to radiolabels or a cytotoxic agent. (Zhao et al., (2005) CANCER RES. 65; 2846-53; Afar et al., (2004) MOL. CANCER THER. 3: 921-32.)
  • TMEFF2 A truncated isoform of TMEFF2 is secreted by prostate cancer cells. (Quayle et al., (2006) GENOMICS 87: 633-37.)
  • the amino acid sequence of a secreted form of TMEFF2, TMEFF2-S, is:
  • F5" is coagulation factor V. It is encoded, for example, by NCBI Entrez GenelD: 2153.
  • An example of the amino acid sequence is published in the NCBI database under the accession number NP 000121 , and is: MFPGCPRLWV LWLGTSWVG WGSQGTEAAQ LRQFYVAAQG ISWSYRPEPT NSSLNLSVTS FKKIVYREYE PYFKKEKPQS TISGLLGPTL YAEVGDIIKV HFKNKADKPL SIHPQGIRYS KLSEGASYLD HTFPAEKMDD AVAPGREYTY EWSISEDSGP THDDPPCLTH IYYSHENLIE DFNSGLIGPL LICKKGTLTE
  • TMPDITVCAH DHISWHLLGM SSGPELFSIH FNGQVLEQNH HKVSAITLVS ATSTTANMTV GPEGKWIISS LTPKHLQAGM QAYIDIKNCP KKTRNLKKIT REQRRHMKRW EYFIAAEEVI WDYAPVIPAN MDKKYRSQHL DNFSNQIGKH YKKVMYTQYE DESFTKHTVN PNMKEDGILG PIIRAQVRDT LKIVFKNMAS RPYSIYPHGV TFSPYEDEVN SSFTSGRNNT MIRAVQPGET YTYKWNILEF DEPTENDAQC LTRPYYSDVD IMRDIASGLI GLLLICKSRS LDRRGIQRAA DIEQQAVFAV FDENKSWYLE DNINKFCENP DEVKRDDPKF YESNIMSTIN GYVPESITTL GFCFDDTVQW HFCSVGTQNE ILTIHFTGHS FIYGKRHEDT
  • Amino acids 1-28 are a signal peptide; thus, the mature F5 protein corresponds to amino acids 29-2224 of SEQ ID NO: 10.
  • F5 is also known as proaccelerin and labile factor.
  • SMOC is SPARC related modular calcium binding. It is encoded, for example, by NCBI Entrez GenelD NOS: 64093 (SMOC1 ) and 64094 (SMOC2). An example of the amino acid sequence of the first isoform of SMOC1 is published in the NCBI database under the accession number NP_001030024, and is:
  • PKNDNWIPE CAHGGLYKPV QCHPSTGYCW CVLVDTGRPI PGTSTRYEQP KCDNTARAHP AKARDLYKGR QLQGCPGAKK HEFLTSVLDA LSTDMVHAAS DPSSSSGRLS EPDPSHTLEE RWHWYFKLL DKNSSGDIGK KEIKPFKRFL RKKSKPKKCV
  • Human SMOC2 has also been reported to include an alternate splice acceptor site, resulting in the expression of two isoforms of human SMOC2. (Vannahme et al. (2003) BIOCHEM. J, 373: 805-14.) The amino acid sequence of the second isoform is:
  • SMOC refers to both SMOC1 and SMOC2, including any isoforms.
  • SMOC2 is also known as smooth muscle associated protein 2 and secreted modular calcium binding protein 2. It can potentiate angiogenesis and endothelial cell migration, and antibodies to this protein have been produced. (Rocnick et al., (2006) J. BIOL. CHEM. 281 :22855-64).
  • LTF lactotransferrin. It is encoded, for example, by NCBI Entrez GenelD: 4057. An example of the amino acid sequence is published in the NCBI database under the accession number NP_002334, and is:
  • ACPP acid phosphatase, prostate. It is encoded, for example, by NCBI Entrez GenelD: 55. An example of the amino acid sequence is published in the NCBI database under the accession number NP_001090, and is:
  • GPVIPQDWST ECMTTNSHQG TEDSTD (SEQ ID NO: 16) .
  • Amino acids 1-32 are a signal peptide. The mature protein corresponds to amino acids 33-386 of SEQ ID NO: 16.
  • ACPP is also known as PAP.
  • TGM4 transglutaminase 4 (prostate). It is encoded, for example, by NCBI Entrez GenelD: 7047. An example of the amino acid sequence is published in the NCBI database under the accession number NPJ303232, and is:
  • MSMB microseminoprotein, beta. There are two alternatively spliced transcript variants encoding different isoforms.
  • the MSMB gene is set forth, for example, in NCBI Entrez GenelD: 4477.
  • An example of the amino acid sequence is published in the NCBI database under the accession number NP_002434, and is:
  • amino acid sequence of isoform b is published in the NCBI database under the accession number NP_619540, and is: MNVLLGSWI FATFVTLCNA SCYFIPNEGV PGDSTRMFLH LWVMTKTTAK ESSRRRTASI SWWRRRTQKR PVLSVNG
  • MSMB seminal plasma beta-inhibin
  • WIF1 WNT inhibitory factor 1. It is encoded, for example, by NCBI Entrez GenelD: 11197. An example of the amino acid sequence is published in the NCBI database under the accession number NP_009122, and is:
  • PSLKKAEERR DPPESNYiw (SEQ ID NO: 20) .
  • Amino acids 1-28 are a signal peptide.
  • the mature protein therefore corresponds to amino acids 29-379 of SEQ ID NO: 20.
  • OFM4 is olfactomedin 4. It is encoded, for example, by NCBI Entrez GenelD: 10562. An example of the amino acid sequence is published in the NCBI database under the accession number NP_006409, and is:
  • INYNPFDQKL YVYNDGYLLN YDLSVLQKPQ (SEQ ID NO: 21 ) .
  • Amino acids 1 -20 are a signal peptide.
  • the mature protein corresponds to amino acids 21-510 of SEQ ID NO: 21.
  • PH 5 is peptidase inhibitor 15. It is encoded, for example, by NCBI Entrez GenelD: 51050. An example of the amino acid sequence is published in the NCBI database under the accession number NP_056970, and is:
  • TDNLCFPGVT SNYLYWFK SNYLYWFK (SEQ ID NO: 22).
  • the mature protein corresponds to amino acids 26-258.
  • Amino acids 1-25 are a signal sequence.
  • PDGFD platelet-derived growth factor D. It is encoded, for example, by NCBI Entrez GenelD: 80310. There are two splice variants for this gene. An example of the amino acid sequence of isoform 1 is published in the NCBI database under the accession number NP_079484, and is:
  • DCicssRPPR (SEQ ID NO: 23). Amino acids 1-23 are signal sequence. Amino acids 24-370 correspond to a mature protein.
  • the signal sequence corresponds to amino acids 1-13, while amino acids 14-364 correspond to a mature protein.
  • PDGFD is also known as iris- expressed growth factor.
  • CHGA chromogranin A. It is encoded, for example, by NCBI Entrez GenelD: 1113. An example of the amino acid sequence is published in the NCBI database under the accession number NP_001266, and is:
  • EAELEKVAHQ LQALRRG (SEQ ID NO: 25).
  • CHGA is the precursor to several polypeptides. When only the signal peptide (amino acids 1-18 of SEQ ID NO: 25) is removed, the polypeptide is called chromogranin A. It corresponds to amino acids 19-457 of SEQ ID NO: 25. Amino acids 19-131 of SEQ ID NO: 25 correspond to the polypeptide called beta-granin. Vasostatin corresponds to amino acids 19-94 of SEQ ID NO: 25. Amino acids 142- 161 of SEQ ID NO: 25 correspond to chromostatin. Pancreastatin is the name given to the polypeptide corresponding to amino acids 268-320 of SEQ ID NO: 25.
  • SEQ ID NO: 22 Other polypeptides contained within SEQ ID NO: 22 include WE-14 (amino acids 342-355), parastatin (amino acids 374-445), and GE-25 (amino acids 393-417). CHGA is also known as parathyroid secretory protein 1.
  • CAV1 is caveolin 1. It is encoded, for example, by NCBI Entrez GenelD: 857. An example of the amino acid sequence is published in the NCBI database under the accession number NP_001744, and is:
  • caveolin is usually an integral membrane protein, it can be found in the medium of cultured human prostate cancer cells, which overexpress this protein. (See, e.g., Tahir et al., (2001 ) CANCER RES. 61 : 3882-85.) The mechanism by which secretion of caveolin occurs is unclear. CAV1 is also known as caveolae protein.
  • RNN1 relaxin 1. It is encoded, for example, by NCBI Entrez GenelD: 6013. Alternative splice forms exists, but these have not been characterized. The encoded protein is synthesized as a single-chain polypeptide but the active form consists of an A chain and a B chain linked by disulfide bonds; however, the exact cleavage sites within the prepropolypeptide have not been described. An example of the amino acid sequence is published in the NCBI database under the accession number NP_008842, and is:
  • RRPYVALFEK CCLIGCTKRS LAKYC (SEQ ID NO: 27).
  • IGFBP7 insulin-like growth factor binding protein 7. It is encoded, for example, by GenelD: 3490. An example of the amino acid sequence is published in the NCBI database under the accession number NP_001544, and is:
  • IGFBP7 is also known as mac25.
  • BGN is biglycan. It is encoded, for example, by NCBI Entrez GenelD: 633. An example of the amino acid sequence is published in the NCBI database under the accession number NP_001702, and is:
  • Amino acids 1-16 of SEQ ID NO: 29 correspond to a signal peptide, while amino acids 17-368 correspond to a propeptide form.
  • the mature protein corresponds to amino acids 38-368 of SEQ ID NO: 29.
  • BGN is also known as dermatan sulphate proteoglycan I.
  • IL6 interleukin 6. It is encoded, for example, by NCBI Entrez GenelD: 3569. An example of the amino acid sequence is published in the NCBI database under the accession no. NP_000591 , and is:
  • IL6 is also known as interferon beta 2.
  • One IL6 target is a prostate-specific G protein receptor.
  • a polymorphism in IL6 is associated with more aggressive prostate cancer (Tan et al. (2005) J. UROL. 174 (2), 753-56) and IL6 has been reported to play a role in prostate cancer progression (Palmer et al. (2004) INT. J. BIOCHEM. CELL BIOL. 36 (11 ), 2258-69; Shariat et al., (2004) CLIN. CANCER RES. 10 (6), 1992-99; Culig et al., (2002) MOL. CELL. ENDOCRINOL. 197 (1-2), 231-38; Giri et al. (2001 ) AM. J. PATHOL. 159 (6), 2159-65).
  • VEGF vascular endothelial growth factor. It is encoded, for example, by NCBI Entrez GenelD: 7422. An example of the amino acid sequence is published in the NCBI database under the accession no. AAH65522, and is:
  • NKCECRPKKD RARQEKCDKP RR (SEQ ID NO: 31).
  • VEGF vascular endothelial growth factor
  • CLIN CANCER RES. 11 :584-93 CLIN CANCER RES. 11 :584-93
  • VEGF may control the metastatic properties of prostate cancer cells (Chen et al., (2004) CELL COMMUN ADHES. 11 :1-11 ).
  • FMOD is fibromodulin. It is encoded, for example, by NCBI Entrez GenelD: 2331. An example of the amino acid sequence is published in the NCBI database under the accession number NP_002014, and is:
  • AGR2 anterior gradient 2 homolog (Xenopus laevis). It is encoded, for example, by NCBI Entrez GenelD: 10551. An example of the amino acid sequence is published in the NCBI database under the accession number NP_006399, and is:
  • LDNMKKALKL LKTEL (SEQ ID NO: 33).
  • SERPINA3 is serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3. It is encoded, for example, by NCBI Entrez GenelD: 12. SERPINA3 encodes a plasma protease inhibitor and member of the serine protease inhibitor class. There are a variety of polymorphisms that appear to be tissue specific and influence protease targeting. An example of the amino acid sequence is published in the NCBI database under the accession number NP_001076, and is:
  • MI IVPTDTQN IFFMSKVTNP KQA (SEQ ID NO: 34) .
  • the signal peptide corresponds to amino acids 1-25 of SEQ ID NO: 34, while amino acids 26-423 correspond to the mature protein.
  • SERPINA3 is also known as alpha-1 -antichymotrypsin.
  • AZGP1 alpha-2-glycoprotein 1 , zinc. It is encoded, for example, by NCBI Entrez GenelD: 563. An example of the amino acid sequence is published in the NCBI database under the accession number NP_001176, and is:
  • HVQHSSLAQP LWPWEAS (SEQ ID NO: 35) .
  • FAM3B is family with sequence similarity 3, member B. It is encoded, for example, by NCBI Entrez GenelD: 54097.
  • An example of the amino acid sequence is published in the NCBI database under the accession number NP_478066, and is: MRPLAGGLLK WFWFASLC AWYSGYLLAE LIPDAPLSSA AYSIRSIGER PVLKAPVPKR QKCDHWTPCP SDTYAYRLLS GGGRSKYAKI CFEDNLLMGE QLGNVARGIN IAIVNYVTGN VTATRCFDMY EGDNSGPMTK FIQSAAPKSL LFMVTYDDGS TRLNNDAKNA IEALGSKEIR NMKFRSSWVF IAAKGLELPS EIQREKINHS DAKNNRYSGW PAEIQIEGCI PKERS
  • FAM3B is also known as cytokine-like protein 2-21 and pancreatic derived factor.
  • CD164 is CD164 antigen, sialomucin. It is encoded, for example, by NCBI Entrez GenelD: 8763. Splice variants exist in which either exon 4 or exon 5 is lacking. (Doyonnas et al., (2000) J. IMMUNOL. 165: 840-51.) An example of an amino acid sequence containing both exon 4 and exon 5 is published in the NCBI database under the accession number NP_006007, and is:
  • the isoform lacking exon 4 has the same amino acid sequence as SEQ ID NO: 37, except that amino acids 111-123 are deleted.
  • the isoform lacking exon 5 has the same amino acid sequence as SEQ ID NO: 37, except that amino acids 124-142 are deleted.
  • a soluble variant has also been described. (Masuzawa et al., (1992) J. BIOL. CHEM. 112: 609-15.)
  • An example of the amino acid sequence of soluble CD164 is:
  • Protein is used interchangeably with the terms “peptide” and “polypeptide” and refers to any chain of amino acids, regardless of length or posttranslational modification (e.g., glycosylation or phosphorylation), or source (e.g., species).
  • antibody refers to an immunoglobulin or fragment thereof, and encompasses any polypeptide comprising an antigen-binding fragment or an antigen-binding domain.
  • the term includes but is not limited to polyclonal, monoclonal, monospecific, polyspecific, humanized, human, single-chain, chimeric, synthetic, recombinant, hybrid, mutated, grafted, and in vitro generated antibodies.
  • the term “antibody” includes antibody fragments such as Fab, F(ab') 2 , Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen-binding function. Unless otherwise specified, an antibody is not necessarily from any particular source, nor is it produced by any particular method.
  • the terms "specific interaction,” “specific binding,” or the like, mean that two molecules form a complex that is relatively stable under physiologic conditions.
  • the term is also applicable where, e.g., an antigen-binding domain is specific for a particular epitope, which is carried by a number of antigens, in which case the specific binding member carrying the antigen-binding domain will be able to bind to the various antigens carrying the epitope.
  • Specific binding is characterized by a high affinity and a low to moderate capacity. Nonspecific binding usually has a low affinity with a moderate to high capacity.
  • the binding is considered specific when the affinity constant K 3 is higher than 10 6 M “1 , more preferably higher than 10 7 M “1 , and most preferably 10 8 M “1 .
  • non-specific binding can be reduced without substantially affecting specific binding by varying the binding conditions.
  • Such conditions are known in the art, and a skilled artisan using routine techniques can select appropriate conditions.
  • the conditions are usually defined in terms of concentration of antibodies, ionic strength of the solution, temperature, time allowed for binding, concentration of non-related molecules (e.g., serum albumin, milk casein), etc.
  • detectably labeled refers to any means for marking and identifying the presence of a molecule, e.g., an antibody or other protein. Methods for labeling a molecule are well known in the art. Labels can be either detectable or functional labels, and include radiolabels (e.g., 131 1, 125 1, 35 S, and 99 Tc), enzymatic labels (e.g., horseradish peroxidase or alkaline phosphatase), chemiluminescent labels, and other chemical moieties (e.g., biotin).
  • radiolabels e.g., 131 1, 125 1, 35 S, and 99 Tc
  • enzymatic labels e.g., horseradish peroxidase or alkaline phosphatase
  • chemiluminescent labels e.g., chemiluminescent labels
  • other chemical moieties e.g., biotin
  • isolated refers to a molecule that is substantially free of its natural environment. Any amount of that molecule elevated over the naturally occurring levels due to any manipulation, e.g., over expression, partial purification, etc., is encompassed with the definition. With regard to partially purified compositions only, the term refers to an isolated compound that is at least 50-70%, 70-90%, 90-95% (w/w), or more pure.
  • a “moderate risk” prostate cancer is cancer in which the patient has, for example, no PSA recurrence, a Gleason score of 6-7, T2a-T3b stage, no seminal vesicle invasion, and well or moderate tumor differentiation.
  • a "high risk" prostate cancer is cancer in which the patient has, for example, PSA recurrence, a Gleason score of 8-9, T3c stage, seminal vesicle invasion, and poor tumor differentiation.
  • the disclosure describes the identification and validation of diagnostic and prognostic biomarkers for prostate cancer, including NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, PU 5, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164.
  • diagnostic biomarkers can be used to diagnose individuals with prostate cancer.
  • These prognostic biomarkers can be used to identify prostate cancer patients who are at risk of developing advanced disease by differentiating between aggressive and non-aggressive courses of cancer development.
  • Each of the secreted proteins, their fragments, or other derivatives can be detected using antibodies or other binding proteins.
  • Commercially available antibodies to a particular secreted protein can be used.
  • the secreted protein, a fragment, or a derivative thereof can be used as an immunogen to generate antibodies that specifically bind that secreted protein.
  • Such antibodies include, but are not limited to, polyclonal antibodies, monoclonal antibodies, chimeric antibodies, single chain antibodies, and antibody fragments.
  • the antibodies may be from mice, rats, rabbits, hamsters, goats, llamas, humans, or other species.
  • adjuvants include, but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum.
  • BCG Bacille Calmette-Guerin
  • corynebacterium parvum examples include, but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum.
  • monoclonal antibodies can be produced using the hybridoma technique (e.g., Kohler et al (1975) Nature, 256:495- 97; and as described in Antibodies: A Laboratory Manual, eds. Harlow et al., Cold Spring Harbor Laboratory, 1988; Current Protocols in Immunology, Chpt. 2; eds. Colligan et al., National Institutes of Health, Published by John Wiley & Sons, Inc., 2006). Antibodies can also be produced using recombinant DNA methods (e.g., U.S.
  • Patent 4,816,567) or using phage display antibody libraries e.g., Clackson et al. (1991 ) Nature, 352: 624-28; Marks et al. (1991 ) J. MoI. Biol., 222: 581-97.
  • chimeric antibodies can be produced using methods known in the art (e.g., Morrison et al. (1984) Proc. Natl Acad. Sci. U.S.A., 81 :6851-55; Neuberger et al. (1984) Nature, 312:604-08; Takeda et al. (1985) Nature, 314:452-54).
  • Single chain antibodies can also be produced (e.g., U.S. Patent No.
  • Human antibodies can be prepared using human hybridomas (Cote et al. (1983) Proc. Natl. Acad. Sci. U.S.A., 80:2026-30), by transforming human B cells with EBV virus in vitro (Cole et al. (1985) Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, pp. 77-96), or by preparing hybridomas from animals transgenic for one or more human immunoglobulin genes (e.g., U.S. Patent No. 5,939,598).
  • Antibody fragments can also be generated using known techniques.
  • Fragments include but are not limited to: F(ab') 2 fragments, which can be produced by pepsin digestion of the antibody molecule; Fab' fragments, which can be generated by reducing the disulfide bridges of the F(ab') 2 fragment; Fab fragments, which can be generated by treating the antibody molecule with papain and a reducing agent; and Fv fragments, including single chain Fv (scFv) fragments.
  • F(ab') 2 fragments which can be produced by pepsin digestion of the antibody molecule
  • Fab' fragments which can be generated by reducing the disulfide bridges of the F(ab') 2 fragment
  • Fab fragments which can be generated by treating the antibody molecule with papain and a reducing agent
  • Fv fragments including single chain Fv (scFv) fragments.
  • nucleic acids encoding the various secreted protein biomarkers are known. Methods of manipulating nucleic acids to express proteins are well known in the art, and include those described in Molecular Cloning, A Laboratory Manual (2nd Ed., Sambrook, Fritsch and Maniatis, Cold Spring Harbor) and Current Protocols in Molecular Biology (Eds. Aufubel, Brent, guitarist, More, Feidman, Smith and Guatemala, Greene Publ. Assoc, Wiley-lnterscience, NY, N.Y., 1992).
  • a suitable cell line is transformed with a DNA sequence encoding that protein under the control of known regulatory sequences.
  • the transformed host cells are cultured and the protein recovered and isolated from the culture medium.
  • the isolated expressed proteins are substantially free from other proteins with which they are co-produced as well as from other contaminants.
  • Suitable cells or cell lines may be mammalian cells, such as Chinese hamster ovary cells (CHO), the monkey kidney COS-1 cell line, or mammalian CV-1 cells.
  • CHO Chinese hamster ovary cells
  • CV-1 mammalian CV-1 cells.
  • Bacterial cells may also be used as suitable hosts for expression of the secreted proteins.
  • E. coli e.g., HB101 , MC1061
  • Various strains of S. subtilis, Pseudomonas, other bacilli and the like may also be used.
  • DNA encoding the propeptide is generally not necessary.
  • yeast cells may also be available as host cells for expression of the secreted protein biomarkers.
  • insect cells may be utilized as host cells in the method of the present invention. See, e.g., Miller et al., Genetic Engineering, 8:277-298 (Plenum Press 1986).
  • a secreted protein biomarker is expressed using a vector that contains a full length DNA sequence encoding the protein and appropriate expression control sequences. Expression control sequences for such vectors are known to those skilled in the art and may be selected depending upon the host cells. Such selection is routine.
  • the secreted protein biomarker is expressed as a fusion protein comprising the protein sequence of the biomarker and, for example, a tag to stabilize the resulting fusion protein or to simplify purification of the secreted protein biomarker.
  • tags are known in the art.
  • Representative examples include sequences which encode a series of histidine residues, the epitope tag FLAG, the Herpes simplex glycoprotein D, beta- galactosidase, maltose binding protein, streptavidin tag or glutathione S- transferase.
  • the disclosure provides methods for diagnosing prostate cancer comprising screening biological samples for one or more of the secreted protein biomarkers of a diagnostic panel.
  • the disclosure describes methods of diagnosing prostate cancer comprising screening biological samples for at least one of the secreted proteins NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and PI15.
  • the method of diagnosing prostate cancer in a subject comprises detecting or measuring in a biological sample from the subject the expression of any one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen secreted proteins chosen from NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and Pl 15, and correlating the expression level of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, or PH 5 with the presence of prostate cancer or a higher predisposition to develop prostate cancer in the subject, wherein an increased expression level of any one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC or a decreased expression of any one of LTF, ACPP
  • the expression levels can be quantified such that increased or decreased expression levels relative to a control sample or other standardized value or numerical range indicate the presence of prostate cancer or a higher predisposition to develop prostate cancer.
  • the increased or decreased expression levels in the methods of the invention may be measured relative to the expression of that secreted protein in a control sample, such as a noncancerous sample from the subject or a sample obtained from a different individual who does not have cancer.
  • Expression of a secreted protein may also be normalized by comparing it to the expression of other cancer-specific markers.
  • a prostate-cell specific marker such as PSA, can be used as a control to compare and/or normalize expression levels of secreted proteins.
  • the method of diagnosing prostate cancer can comprise measuring the expression levels of one or more of the secreted proteins NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, and SMOC, where an increased expression level of one or more of the secreted proteins NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, and SMOC of at least 10% as compared to the control sample indicates the presence of prostate cancer.
  • a decreased expression of one or more of the secreted proteins LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and Pl 15 of at least 10% as compared to the control sample indicates the presence of prostate cancer.
  • increases and decreases of at least 10% relative to a control can be used in the diagnostic methods, other values may also be used.
  • the increase or decrease may be at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or even 500%.
  • the increase or decrease may also be expressed in terms of statistical significance, such as p ⁇ 0.05, p ⁇ 0.01 , p ⁇ 0.005, or p ⁇ 0.001 , particularly when large numbers of controls are available for comparison.
  • PSA, %fPSA, PSA doubling time, PSA velocity, prostate volume, or a combination of these indicators is determined in addition.
  • the diagnostic assay is conducted with the proviso that PSA, %fPSA, PSA doubling time, PSA velocity, prostate volume, or a combination thereof, are not determined or measured at the same time.
  • the diagnostic assay can be conducted on a biological sample with the proviso that either PSA or %fPSA, or both, are measured using a different biological sample.
  • the biological samples can be tissue, including prostate tissue, or a biofluid.
  • biofluids include serum, plasma, whole blood, urine, saliva, and prostatic fluid.
  • the biological sample is post-digital rectal exam (post-DRE) urine.
  • Biological samples can be screened using methods known in the art, including, for example, antibody-based assays such as reverse phase protein arrays or ELISA.
  • antibody-based assays such as reverse phase protein arrays or ELISA.
  • an immunoassay is carried out by a method comprising contacting a sample with at least two antibodies, wherein each antibody binds to a different protein in the diagnostic panel. The binding of the antibody to the protein is then detected or measured using techniques known in the art.
  • the immunoassays which can be used include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA, protein arrays, reverse-phase protein arrays, immunoprecipitation assays, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, to name but a few.
  • ELISAs are particularly simple assays that can be used to detect or measure expression levels of proteins.
  • Kits for diagnostic use are also provided.
  • Each kit provides a combination of reagents, where each reagent detects or measures the level of one secreted protein in the diagnostic panel.
  • the reagent can be an antibody or binding protein that binds to a secreted protein of the diagnostic panel, or it can be a substrate for the secreted protein if the secreted protein is an enzyme.
  • Each reagent can be detectably labeled, or a second reagent can be included that detects binding of the antibody or binding protein to the secreted protein. Examples of such second reagents include labeled antibodies that bind the light chain or heavy chain of the anti-secreted protein antibody (e.g., alkaline phosphatase labeled anti-kappa or anti-lgG antibodies).
  • the antibody, binding protein, or substrate that is used to detect or measure the corresponding secreted protein of the diagnostic panel is considered a primary reagent.
  • the diagnostic kit comprises primary reagents that detect or measure levels of one or more of the secreted proteins NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the diagnostic kit comprises primary reagents for detecting or measuring the expression of any one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen secreted proteins chosen from NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and PI15.
  • kits can also comprise a purified, predetermined amount of each secreted protein to be detected or measured using the kit. These purified secreted proteins serve as standards or controls.
  • the kit can also comprise one or more components for detecting the primary reagent, including components described in the examples of this application or known in the art.
  • nucleic acids, polypeptides, and antibodies for use in diagnosing and prognosing prostate cancer are generally formulated with a pharmaceutically acceptable carrier.
  • a nucleic acid, polypeptide, or antibody is part of a kit, an agent that reduces or inhibits the growth of microorganisms, such as sodium azide, can optionally be included in the formulation.
  • the disclosure provides diagnostic methods and kits for detecting one or more of the secretory proteins NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise NPY and SPOCK and optionally at least one of CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise NPY and CRISP3 and optionally at least one of SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise NPY and PLA2G7 and optionally at least one of SPOCK, CRISP3, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise NPY and TMEFF2 and optionally at least one of SPOCK, CRISP3, PLA2G7, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise NPY and F5 and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC. In another embodiment, the secretory proteins to be detected comprise NPY and SMOC and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise NPY and LTF and optionally at least one of ACPP, TGM4, MSMB 1 WIFI , OLFM4, or PI15.
  • the secretory proteins to be detected comprise NPY and ACPP and optionally at least one of LTF, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise NPY and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise NPY and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise NPY and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise NPY and OLFM4 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or PM 5. In another embodiment, the secretory proteins to be detected comprise NPY and Pl 15 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise NPY, at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise SPOCK and NPY and optionally at least one of CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise SPOCK and CRISP3 and optionally at least one of NPY, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise SPOCK and PLA2G7 and optionally at least one of NPY, CRISP3, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise SPOCK and TMEFF2 and optionally at least one of NPY, CRISP3, PLA2G7, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise SPOCK and F5 and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, or SMOC. In another embodiment, the secretory proteins to be detected comprise SPOCK and SMOC and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise SPOCK and LTF and optionally at least one of ACPP, TGM4, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise SPOCK and ACPP and optionally at least one of LTF, TGM4, MSMB 1 WIFI , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise SPOCK and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise SPOCK and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , OLFM4, or PI15. In another embodiment, the secretory proteins to be detected comprise SPOCK and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise SPOCK and OLFM4 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or PM 5. In another embodiment, the secretory proteins to be detected comprise SPOCK and PU 5 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise SPOCK, at least one of NPY, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB, WIF1. OLFM4, or PI15.
  • the secretory proteins to be detected comprise CRISP3 and NPY and optionally at least one of SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise CRISP3 and SPOCK and optionally at least one of NPY, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise CRISP3 and PLA2G7 and optionally at least one of NPY, SPOCK, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise CRISP3 and TMEFF2 and optionally at least one of NPY, SPOCK, PLA2G7, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise CRISP3 and F5 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, or SMOC. In another embodiment, the secretory proteins to be detected comprise CRISP3 and SMOC and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise CRISP3 and LTF and optionally at least one of ACPP, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise CRISP3 and ACPP and optionally at least one of LTF, TGM4, MSMB 1 WIFI , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise CRISP3 and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise CRISP3 and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , OLFM4, or Pl 15. In another embodiment, the secretory proteins to be detected comprise CRISP3 and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, OLFM4, or PM 5.
  • the secretory proteins to be detected comprise CRISP3 and OLFM4 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or Pl 15, In another embodiment, the secretory proteins to be detected comprise CRISP3 and PM 5 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise CRISP3, at least one of NPY, SPOCK, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB, WIF1. OLFM4, or PM 5.
  • the secretory proteins to be detected comprise PLA2G7 and NPY and optionally at least one of SPOCK, CRISP3, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise PLA2G7 and SPOCK and optionally at least one of NPY, CRISP3, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise PLA2G7 and CRISP3 and optionally at least one of NPY, SPOCK, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise PLA2G7 and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise PLA2G7 and F5 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, or SMOC. In another embodiment, the secretory proteins to be detected comprise PLA2G7 and SMOC and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, or F5.
  • the secretory proteins to be detected comprise PLA2G7 and LTF and optionally at least one of ACPP, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise PLA2G7 and ACPP and optionally at least one of LTF, TGM4, MSMB 1 WIFI , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise PLA2G7 and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise PLA2G7 and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise PLA2G7 and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, OLFM4, or PM 5.
  • the secretory proteins to be detected comprise PLA2G7 and OLFM4 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or Pl 15.
  • the secretory proteins to be detected comprise PLA2G7 and Pl 15 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise PLA2G7, at least one of NPY, SPOCK, CRISP3, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB, WIF1. OLFM4, or PI15.
  • the secretory proteins to be detected comprise TMEFF2 and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, F5, or SMOC
  • the secretory proteins to be detected comprise TMEFF2 and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, F5, or SMOC
  • the secretory proteins to be detected comprise TMEFF2 and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, F5, or SMOC.
  • the secretory proteins to be detected comprise TMEFF2 and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise TMEFF2 and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, or SMOC. In another embodiment, the secretory proteins to be detected comprise TMEFF2 and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, or F5.
  • the secretory proteins to be detected comprise TMEFF2 and LTF and optionally at least one of ACPP, TGM4, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise TMEFF2 and ACPP and optionally at least one of LTF, TGM4, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise TMEFF2 and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise TMEFF2 and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , OLFM4, or Pl 15. In another embodiment, the secretory proteins to be detected comprise TMEFF2 and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, OLFM4, or Pl 15. In another embodiment, the secretory proteins to be detected comprise TMEFF2 and OLFM4 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or Pl 15. In another embodiment, the secretory proteins to be detected comprise TMEFF2 and P115 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise TMEFF2, at least one of NPY, SPOCK, CRISP3, PLA2G7, F5, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB, WIF1. OLFM4, or PI15.
  • the secretory proteins to be detected comprise F5 and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC.
  • the secretory proteins to be detected comprise F5 and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, or SMOC.
  • the secretory proteins to be detected comprise F5 and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, or SMOC.
  • the secretory proteins to be detected comprise F5 and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, or SMOC. In another embodiment, the secretory proteins to be detected comprise F5 and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, or SMOC. In another embodiment, the secretory proteins to be detected comprise F5 and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, or TMEFF2.
  • the secretory proteins to be detected comprise F5 and LTF and optionally at least one of ACPP, TGM4, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise F5 and ACPP and optionally at least one of LTF, TGM4, MSMB, WIF1 , OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise F5 and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise F5 and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , OLFM4, or Pl 15. In another embodiment, the secretory proteins to be detected comprise F5 and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, OLFM4, or Pl 15. In another embodiment, the secretory proteins to be detected comprise F5 and OLFM4 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or PM 5. In another embodiment, the secretory proteins to be detected comprise F5 and Pl 15 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise F5, at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise SMOC and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise SMOC and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise SMOC and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise SMOC and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, or F5.
  • the secretory proteins to be detected comprise SMOC and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, or F5.
  • the secretory proteins to be detected comprise SMOC and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, or TMEFF2.
  • the secretory proteins to be detected comprise SMOC and LTF and optionally at least one of ACPP, TGM4, MSMB, WIF1 , OLFM4, or Pl 15,
  • the secretory proteins to be detected comprise SMOC and ACPP and optionally at least one of LTF, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise SMOC and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise SMOC and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise SMOC and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise SMOC and OLFM4 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or PM 5. In another embodiment, the secretory proteins to be detected comprise SMOC and Pl 15 and optionally at least one of LTF, ACPP, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise SMOC, at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or F5, and at least one of LTF, ACPP, TGM4, MSMB, WIF1. OLFM4, or PI15.
  • the secretory proteins to be detected comprise LTF and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise LTF and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise LTF and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise LTF and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise LTF and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, F5, or SMOC.
  • the secretory proteins to be detected comprise LTF and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC.
  • the secretory proteins to be detected comprise LTF and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise LTF and ACPP and optionally at least one of TGM4, MSMB 1 WIFI , OLFM4, or PI15.
  • the secretory proteins to be detected comprise LTF and TGM4 and optionally at least one of ACPP, MSMB, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise LTF and MSMB and optionally at least one of ACPP, TGM4, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise LTF and WIF1 and optionally at least one of ACPP, TGM4, MSMB, OLFM4, or PM 5.
  • the secretory proteins to be detected comprise LTF and OLFM4 and optionally at least one of ACPP, TGM4, MSMB, WIF1 , or Pl 15. In another embodiment, the secretory proteins to be detected comprise LTF and Pl 15 and optionally at least one of ACPP, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise LTF, at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of ACPP, TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise ACPP and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise ACPP and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise ACPP and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise ACPP and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise ACPP and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, F5, or SMOC.
  • the secretory proteins to be detected comprise ACPP and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC.
  • the secretory proteins to be detected comprise ACPP and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise ACPP and LTF and optionally at least one of TGM4, MSMB, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise ACPP and TGM4 and optionally at least one of LTF, MSMB, WIF1 , OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise ACPP and MSMB and optionally at least one of LTF, TGM4, WIF1 , OLFM4, or PM 5.
  • the secretory proteins to be detected comprise ACPP and WIF1 and optionally at least one of LTF, TGM4, MSMB, OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise ACPP and OLFM4 and optionally at least one of LTF, TGM4, MSMB, WIF1 , or Pl 15. In another embodiment, the secretory proteins to be detected comprise ACPP and PM 5 and optionally at least one of LTF, TGM4, MSMB, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise ACPP, at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, TGM4, MSMB, WIF1. 0LFM4, or PI15.
  • the secretory proteins to be detected comprise TGM4 and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise TGM4 and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise TGM4 and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise TGM4 and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise TGM4 and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise TGM4 and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC. In another embodiment, the secretory proteins to be detected comprise TGM4 and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise TGM4 and LTF and optionally at least one of ACPP, MSMB 1 WIFI , OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise TGM4 and ACPP and optionally at least one of LTF, MSMB, WIF1 , OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise TGM4 and MSMB and optionally at least one of LTF, ACPP, WIF1 , OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise TGM4 and WIF1 and optionally at least one of LTF, ACPP, MSMB, OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise TGM4 and OLFM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , or PM 5. In another embodiment, the secretory proteins to be detected comprise TGM4 and Pl 15 and optionally at least one of LTF, ACPP, MSMB 1 WIFI , or OLFM4.
  • the secretory proteins to be detected comprise TGM4, at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, MSMB, WIF1. OLFM4, or PI15.
  • the secretory proteins to be detected comprise MSMB and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise MSMB and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise MSMB and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise MSMB and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise MSMB and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, F5, or SMOC.
  • the secretory proteins to be detected comprise MSMB and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC.
  • the secretory proteins to be detected comprise MSMB and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise MSMB and LTF and optionally at least one of ACPP, TGM4, WIF1 , OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise MSMB and ACPP and optionally at least one of LTF, TGM4, WIF1 , OLFM4, or PM 5. In another embodiment, the secretory proteins to be detected comprise MSMB and TGM4 and optionally at least one of LTF, ACPP, WIF1 , OLFM4, or Pl 15. In another embodiment, the secretory proteins to be detected comprise MSMB and WIF1 and optionally at least one of LTF, ACPP, TGM4, OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise MSMB and OLFM4 and optionally at least one of LTF, ACPP, TGM4, WIF1 , or Pl 15. In another embodiment, the secretory proteins to be detected comprise MSMB and Pl 15 and optionally at least one of LTF, ACPP, TGM4, WIF1 , or OLFM4.
  • the secretory proteins to be detected comprise MSMB, at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, TGM4, WIF1 , OLFM4, or PI15.
  • the secretory proteins to be detected comprise Wl F1 and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise WIF1 and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise WIF1 and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise WIF1 and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise WIF1 and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, F5, or SMOC.
  • the secretory proteins to be detected comprise WIF1 and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC.
  • the secretory proteins to be detected comprise WIF1 and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise Wl F1 and LTF and optionally at least one of ACPP, TGM4, MSMB, OLFM4, or PU 5.
  • the secretory proteins to be detected comprise WIF1 and ACPP and optionally at least one of LTF, TGM4, MSMB, OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise WIF1 and TGM4 and optionally at least one of LTF, ACPP, MSMB, OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise Wl F1 and MSMB and optionally at least one of LTF, ACPP, TGM4, OLFM4, or Pl 15.
  • the secretory proteins to be detected comprise Wl F1 and OLFM4 and optionally at least one of LTF, ACPP, TGM4, MSMB, or Pl 15. In another embodiment, the secretory proteins to be detected comprise Wl F1 and Pl 15 and optionally at least one of LTF, ACPP, TGM4, MSMB, or OLFM4.
  • the secretory proteins to be detected comprise WIF1 , at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB, OLFM4, or PI15.
  • the secretory proteins to be detected comprise OLMF4 and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise OLMF4 and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise OLMF4 and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise OLMF4 and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise OLMF4 and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise OLMF4 and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC.
  • the secretory proteins to be detected comprise OLMF4 and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise OLMF4 and LTF and optionally at least one of ACPP, TGM4, MSMB, WIF1 , or Pl 15.
  • the secretory proteins to be detected comprise OLMF4 and ACPP and optionally at least one of LTF, TGM4, MSMB 1 WIFI , or Pl 15.
  • the secretory proteins to be detected comprise OLMF4 and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , or Pl 15. In another embodiment, the secretory proteins to be detected comprise OLMF4 and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , or Pl 15. In another embodiment, the secretory proteins to be detected comprise OLMF4 and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, or Pl 15. In another embodiment, the secretory proteins to be detected comprise OLMF4 and Pl 15 and optionally at least one of LTF, ACPP, TGM4, MSMB, or WIFL
  • the secretory proteins to be detected comprise OLMF4, at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB, WIF1 or PI15.
  • the secretory proteins to be detected comprise PM 5 and NPY and optionally at least one of SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise Pl 15 and SPOCK and optionally at least one of NPY, CRISP3, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise Pl 15 and CRISP3 and optionally at least one of NPY, SPOCK, PLA2G7, TMEFF2, F5, or SMOC.
  • the secretory proteins to be detected comprise Pl 15 and PLA2G7 and optionally at least one of NPY, SPOCK, CRISP3, TMEFF2, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise Pl 15 and TMEFF2 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, F5, or SMOC. In another embodiment, the secretory proteins to be detected comprise Pl 15 and F5 and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or SMOC. In another embodiment, the secretory proteins to be detected comprise Pl 15 and SMOC and optionally at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, or F5.
  • the secretory proteins to be detected comprise Pl 15 and LTF and optionally at least one of ACPP, TGM4, MSMB, WIF1 , or OLMF4. In another embodiment, the secretory proteins to be detected comprise Pl 15 and ACPP and optionally at least one of LTF, TGM4, MSMB, WIF1 , or OLMF4. In another embodiment, the secretory proteins to be detected comprise PU 5 and TGM4 and optionally at least one of LTF, ACPP, MSMB, WIF1 , or OLMF4. In another embodiment, the secretory proteins to be detected comprise PM 5 and MSMB and optionally at least one of LTF, ACPP, TGM4, WIF1 , or OLMF4.
  • the secretory proteins to be detected comprise Pl 15 and WIF1 and optionally at least one of LTF, ACPP, TGM4, MSMB, or OLMF4, In another embodiment, the secretory proteins to be detected comprise Pl 15 and OLMF4 and optionally at least one of LTF, ACPP, TGM4, MSMB, or WIF1.
  • the secretory proteins to be detected comprise PM 5, at least one of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, or SMOC, and at least one of LTF, ACPP, TGM4, MSMB 1 WIFI or OLMF4.
  • the disclosure provides methods for prognosing prostate cancer comprising screening biological samples for one or more of the secreted protein biomarkers of a prognostic panel.
  • the disclosure describes methods of prognosing prostate cancer comprising screening biological samples for one or more of the secreted proteins SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the method of prognosing prostate cancer in a subject comprises detecting or measuring in a biological sample from the subject the expression of any one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen secreted proteins chosen from SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164, wherein an increased expression level of any one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF or a decreased expression level of any one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164 correlates with prostate cancer progression or severity, such as whether the prostate cancer is a moderate risk prostate cancer or a high risk prostate cancer, whether the
  • the expression levels can be quantified such that increased or decreased expression levels relative to a control sample or other standardized value or numerical range indicate an increased disease severity, such as high risk prostate cancer, or decreased disease-free survival following radical prostatectomy.
  • the increased or decreased expression levels in the methods of the invention may be measured relative to the expression of that secreted protein in a control sample, such as a noncancerous sample from the subject or a sample obtained from a different individual who does not have cancer.
  • Expression of a secreted protein may also be normalized by comparing it to the expression of other cancer-specific markers.
  • a prostate-cell specific marker such as PSA, can be used as a control to compare and/or normalize expression levels of secreted proteins.
  • the method of prognosing prostate cancer can comprise measuring the expression levels of one or more of the secreted proteins SPOCK, PDGFD, CHGA, CAV1 , RLN 1 , IGFBP7, BGN, IL6, and VEGF, where an increased expression level of one or more of the secreted proteins SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF of at least 10% as compared to the control sample indicates a higher predisposition to develop prostate cancer, prostate cancer progression, or disease severity.
  • a decreased expression of one or more of the secreted proteins LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164 of at least 10% as compared to the control sample indicates a higher predisposition to develop prostate cancer, prostate cancer progression, or disease severity.
  • increases and decreases of at least 10% relative to a control can be used in the prognostic methods, other values may also be used.
  • the increase or decrease may be at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or even 500%.
  • the increase or decrease may also be expressed in terms of statistical significance, such as p ⁇ 0.05, p ⁇ 0.01 , p ⁇ 0.005, or p ⁇ 0.001.
  • PSA, %fPSA, PSA doubling time, PSA velocity, prostate volume, or a combination of these indicators is determined in addition.
  • the prognostic assay is conducted with the proviso that PSA, %fPSA, PSA doubling time, PSA velocity, prostate volume, or a combination thereof, are not determined or measured at the same time.
  • the prognostic assay can be conducted on a biological sample with the proviso that either PSA or %fPSA, or both, are measured using a different biological sample.
  • the biological samples can be screened in the prognostic assays as described for the diagnostic assays.
  • the biological samples can be tissue, including prostate tissue, or a biofluid.
  • biofluids include serum, plasma, whole blood, urine, saliva, and prostatic fluid.
  • the biological sample is post-digital rectal exam (post-DRE) urine.
  • Kits for prognostic use are also provided and these kits comprise the same basic components as the diagnostic kits, except that the primary reagents differ. As discussed for the diagnostic kits, the prognostic kits may also comprise standards or controls. In the prognostic kits, the primary reagents detect or measure levels of one or more of the secreted proteins SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the primary reagents detect or measure levels of one or more of the secreted proteins SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the prognostic kits comprise primary reagents for detecting or measuring the expression of any one two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen secreted proteins chosen from SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164.
  • the disclosure provides prognostic methods and kits for detecting one or more of the secretory proteins SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise SPOCK and PDGFD and optionally at least one of CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SPOCK and CHGA and optionally at least one of PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SPOCK and CAV1 and optionally at least one of PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SPOCK and RLN1 and optionally at least one of PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise SPOCK and IGFBP7 and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise SPOCK and BGN and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise SPOCK and IL6 and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or VEGF. In another embodiment, the secretory proteins to be detected comprise SPOCK and VEGF and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or IL6.
  • the secretory proteins to be detected comprise SPOCK and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise SPOCK and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise SPOCK and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise SPOCK and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise SPOCK and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise SPOCK and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise SPOCK and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise SPOCK, at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise PDGFD and SPOCK and optionally at least one of CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise PDGFD and CHGA and optionally at least one of SPOCK, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise PDGFD and CAV1 and optionally at least one of SPOCK, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise PDGFD and RLN1 and optionally at least one of SPOCK, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise PDGFD and IGFBP7 and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise PDGFD and BGN and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , or IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise PDGFD and IL6 and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or VEGF. In another embodiment, the secretory proteins to be detected comprise PDGFD and VEGF and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or IL6..
  • the secretory proteins to be detected comprise PDGFD and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise PDGFD and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise PDGFD and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise PDGFD and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise PDGFD and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise PDGFD and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise PDGFD and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise PDGFD, at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CHGA and SPOCK and optionally at least one of PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CHGA and PDGFD and optionally at least one of SPOCK, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CHGA and CAV1 and optionally at least one of SPOCK, PDGFD, RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CHGA and RLN1 and optionally at least one of SPOCK, PDGFD, CAV1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise CHGA and IGFBP7 and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise CHGA and BGN and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise CHGA and IL6 and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, or VEGF. In another embodiment, the secretory proteins to be detected comprise CHGA and VEGF and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, or IL6.
  • the secretory proteins to be detected comprise CHGA and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CHGA and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CHGA and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CHGA and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CHGA and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise CHGA and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise CHGA and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise CHGA, at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CAV1 and SPOCK and optionally at least one of PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CAV1 and PDGFD and optionally at least one of SPOCK, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CAV1 and CHGA and optionally at least one of SPOCK, PDGFD, RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CAV1 and RLN1 and optionally at least one of SPOCK, PDGFD, CHGA, IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise CAV1 and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise CAV1 and BGN and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise CAV1 and IL6 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, or VEGF. In another embodiment, the secretory proteins to be detected comprise CAV1 and VEGF and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, or IL6.
  • the secretory proteins to be detected comprise CAV1 and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CAV1 and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CAV1 and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise CAV1 and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise CAV1 and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise CAV1 and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164. In another embodiment, the secretory proteins to be detected comprise CAV1 and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise CAV1 , at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise RLN 1 and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise RLN 1 and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise RLN 1 and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise RLN 1 and CAV1 and optionally at least one of SPOCK 1 PDGFD, CHGA, IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise RLN1 and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise RLN1 and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise RLN1 and IL6 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, or VEGF. In another embodiment, the secretory proteins to be detected comprise RLN 1 and VEGF and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, or IL6.
  • the secretory proteins to be detected comprise RLN 1 and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise RLN 1 and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise RLN 1 and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise RLN1 and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise RLN1 and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise RLN1 and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise RLN1 and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise RLN1 , at least one of SPOCK, PDGFD, CHGA 1 CAV1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise IGFBP7 and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise IGFBP7 and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise IGFBP7 and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise IGFBP7 and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise IGFBP7 and RLN1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise IGFBP7 and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IL6, or VEGF.
  • the secretory proteins to be detected comprise IGFBP7 and IL6 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, or VEGF. In another embodiment, the secretory proteins to be detected comprise IGFBP7 and VEGF and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, or IL6.
  • the secretory proteins to be detected comprise IGFBP7 and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise IGFBP7 and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise IGFBP7 and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise IGFBP7 and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise IGFBP7 and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise IGFBP7 and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164. In another embodiment, the secretory proteins to be detected comprise IGFBP7 and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise IGFBP7, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise BGN and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise BGN and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise BGN and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise BGN and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise BGN and RLN1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise BGN and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IL6, or VEGF.
  • the secretory proteins to be detected comprise BGN and IL6 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, or VEGF. In another embodiment, the secretory proteins to be detected comprise BGN and VEGF and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, or IL6.
  • the secretory proteins to be detected comprise BGN and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise BGN and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise BGN and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise BGN and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise BGN and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPI NA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise BGN and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise BGN and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise BGN, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise IL6 and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or VEGF.
  • the secretory proteins to be detected comprise IL6 and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or VEGF.
  • the secretory proteins to be detected comprise IL6 and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, or VEGF.
  • the secretory proteins to be detected comprise IL6 and CAV1 and optionally at least one of SPOCK 1 PDGFD, CHGA, RLN1 , IGFBP7, BGN, or VEGF. In another embodiment, the secretory proteins to be detected comprise IL6 and RLN1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, or VEGF. In another embodiment, the secretory proteins to be detected comprise IL6 and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1, RLN1 , BGN, or VEGF.
  • the secretory proteins to be detected comprise IL6 and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, or VEGF. In another embodiment, the secretory proteins to be detected comprise IL6 and VEGF and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, or BGN. [0173] In another embodiment of the prognostic methods and kits, the secretory proteins to be detected comprise IL6 and LTF and optionally at least one of FMOD 1 AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise IL6 and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise IL6 and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise IL6 and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise IL6 and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise IL6 and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164. In another embodiment, the secretory proteins to be detected comprise IL6 and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise IL6, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1. FAM3B, or CD164.
  • the secretory proteins to be detected comprise VEGF and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or IL6.
  • the secretory proteins to be detected comprise VEGF and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or IL6.
  • the secretory proteins to be detected comprise VEGF and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, or IL6.
  • the secretory proteins to be detected comprise VEGF and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, or IL6. In another embodiment, the secretory proteins to be detected comprise VEGF and RLN1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, or IL6. In another embodiment, the secretory proteins to be detected comprise VEGF and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, or IL6.
  • the secretory proteins to be detected comprise VEGF and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, or IL6. In another embodiment, the secretory proteins to be detected comprise VEGF and IL6 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, or BGN.
  • the secretory proteins to be detected comprise VEGF and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise VEGF and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise VEGF and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , FAM3B, or CD164, In another embodiment, the secretory proteins to be detected comprise VEGF and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise VEGF and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise VEGF and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164. In another embodiment, the secretory proteins to be detected comprise VEGF and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise VEGF, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, or IL6, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise LTF and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise LTF and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise LTF and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise LTF and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise LTF and RLN 1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise LTF and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise LTF and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1. IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise LTF and FMOD and optionally at least one of AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise LTF and AGR2 and optionally at least one of FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise LTF and SERPI NA3 and optionally at least one of FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise LTF and AZGP1 and optionally at least one of FMOD, AGR2, SERPINA3, FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise LTF and FAM3B and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , or CD164. In another embodiment, the secretory proteins to be detected comprise LTF and CD164 and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise LTF, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise FMOD and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise FMOD and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise FMOD and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise FMOD and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise FMOD and RLN 1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise FMOD and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise FMOD and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise FMOD and LTF and optionally at least one of AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise FMOD and AGR2 and optionally at least one of LTF, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise FMOD and SERPI NA3 and optionally at least one of LTF, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise FMOD and AZGP1 and optionally at least one of LTF AGR2, SERPINA3, FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise FMOD and FAM3B and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , or CD164. In another embodiment, the secretory proteins to be detected comprise FMOD and CD164 and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise FMOD, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, AGR2, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise AGR2 and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise AGR2 and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise AGR2 and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise AGR2 and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise AGR2 and RLN 1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise AGR2 and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise AGR2 and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1. IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise AGR2 and LTF and optionally at least one of FMOD, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise AGR2 and FMOD and optionally at least one of LTF, SERPINA3, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise AGR2 and SERPINA3 and optionally at least one of LTF, FMOD, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise AGR2 and AZGP1 and optionally at least one of LTF, FMOD, SERPINA3, FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise AGR2 and FAM3B and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , or CD164. In another embodiment, the secretory proteins to be detected comprise AGR2 and CD164 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise AGR2, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, SERPINA3, AZGP1. FAM3B, or CD164.
  • the secretory proteins to be detected comprise SERPI NA3 and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SERPI NA3 and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SERPINA3 and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SERPINA3 and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SERPINA3 and RLN1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SERPINA3 and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise SERPINA3 and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise SERPI NA3 and LTF and optionally at least one of FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise SERPINA3 and FMOD and optionally at least one of LTF, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise SERPI NA3 and AGR2 and optionally at least one of LTF, FMOD, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise SERPI NA3 and AZGP1 and optionally at least one of LTF, FMOD, AGR2, FAM3B, or CD164.
  • the secretory proteins to be detected comprise SERPINA3 and FAM3B and optionally at least one of LTF, FMOD, AGR2, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise SERPI NA3 and CD164 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise SERPI NA3, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, AZGP1 , FAM3B, or CD164.
  • the secretory proteins to be detected comprise AZGP1 and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise AZGP1 and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise AZGP1 and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise AZGP1 and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise AZGP 1 and RLN 1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise AZGP1 and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise AZGP1 and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise AZGP1 and LTF and optionally at least one of FMOD, AGR2, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise AZGP1 and FMOD and optionally at least one of LTF, AGR2, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise AZGP1 and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise AZGP1 and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, FAM3B, or CD164. In another embodiment, the secretory proteins to be detected comprise AZGP1 and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, or CD164. In another embodiment, the secretory proteins to be detected comprise AZGP1 and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, or FAM3B.
  • the secretory proteins to be detected comprise AZGP1 , at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, FAM3B, or CD164.
  • the secretory proteins to be detected comprise FAM3B and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise FAM3B and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise FAM3B and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise FAM3B and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise FAM3B and RLN 1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise FAM3B and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise FAM3B and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise FAM3B and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise FAM3B and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise FAM3B and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise FAM3B and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , or CD164. In another embodiment, the secretory proteins to be detected comprise FAM3B and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, or CD164. In another embodiment, the secretory proteins to be detected comprise FAM3B and CD164 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, or AZGP1.
  • the secretory proteins to be detected comprise FAM3B, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or CD164.
  • the secretory proteins to be detected comprise CD164 and SPOCK and optionally at least one of PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CD164 and PDGFD and optionally at least one of SPOCK, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CD164 and CHGA and optionally at least one of SPOCK, PDGFD, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise CD164 and CAV1 and optionally at least one of SPOCK, PDGFD, CHGA, RLN1 , IGFBP7, BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise CD 164 and RLN 1 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , IGFBP7, BGN, IL6, or VEGF.
  • the secretory proteins to be detected comprise CD164 and IGFBP7 and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN 1 , BGN, IL6, or VEGF. In another embodiment, the secretory proteins to be detected comprise CD164 and BGN and optionally at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, IL6, or VEGF.
  • the secretory proteins to be detected comprise CD164 and LTF and optionally at least one of FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise CD164 and FMOD and optionally at least one of LTF, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise CD164 and AGR2 and optionally at least one of LTF, FMOD, SERPINA3, AZGP1 , or FAM3B.
  • the secretory proteins to be detected comprise CD164 and SERPINA3 and optionally at least one of LTF, FMOD, AGR2, AZGP1 , or FAM3B. In another embodiment, the secretory proteins to be detected comprise CD164 and AZGP1 and optionally at least one of LTF, FMOD, AGR2, SERPINA3, or FAM3B. In another embodiment, the secretory proteins to be detected comprise CD164 and FAM3B and optionally at least one of LTF, FMOD, AGR2, SERPINA3, or AZGP1.
  • the secretory proteins to be detected comprise CD164, at least one of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, or VEGF, and at least one of LTF, FMOD, AGR2, SERPINA3, AZGP1 , or FAM3B.
  • ANN models are well-suited for studies using multiple biomarkers. (Stephan et al., (2006) PROSTATE 66: 651-59; Sargent et al., (2001 ) CANCER 91 (8 Suppl): 1636-42.) ANN models are particularly advantageous when the data sets are large because they have the ability to resolve complex, non-linear relationships among variables (e.g. individual protein expression level, clinical factors) without the need to make prior assumptions.
  • the disclosure provides ANN models in which the input data are based upon the presence or levels of one or more secreted biomarkers from Table 1 and/or Table 2 in a biofluid of the patient.
  • This approach is advantageous for several reasons.
  • secreted biomarkers can be measured in biofluids, which are much easier to obtain than is a biopsy sample.
  • secreted biomarkers can be measured objectively using standardized assays, such as ELISA. This helps to minimize variation between different users. Further, combining biomarkers helps to minimize the impact of outlier input data on the output.
  • the disclosure provides a computer-implemented method for diagnosing prostate cancer comprising: identifying one or more of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC,
  • LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and PM 5 as parameters; receiving initial data values for the identified parameters from a patient with a known disease status; training an artificial neural network using the parameters and received initial data; modifying a template using learning gained by the artificial neural network; and using the modified template to diagnose a new patient based on new input values.
  • each of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC, LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and PM 5 is identified as a parameter.
  • the disclosure also provides a computer readable medium including computer code for causing a processor to perform the steps of: identifying one or more of NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC,
  • LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and PM 5 as parameters; receiving initial data values for the identified parameters from a patient with a known disease status; training an artificial neural network using the parameters and received initial data; modifying a template using learning gained by the artificial neural network; and using the modified template to diagnose a new patient based on new input values.
  • initial model development can utilize established clinical factors, such as PSA, %fPSA, PSA doubling time, PSA velocity, PSA recurrence, and prostate volume to find an optimum number of hidden layers.
  • the ANN models can then be trained using biomarker data that is associated with a known clinical outcome.
  • Bayesian regularization developed by Finne et al. ((2000) UROLOGY 56: 418-22) can be used during the training run.
  • diagnostic ANN are trained with data, optionally normalized or scaled, for one or more of the secreted protein biomarkers NPY, SPOCK, CRISP3, PLA2G7, TMEFF2, F5, SMOC LTF, ACPP, TGM4, MSMB, WIF1 , OLFM4, and PM 5.
  • Training may optionally further comprise inclusion of data for one or more of PSA, %fPSA, PSA doubling time, PSA velocity, PSA recurrence, prostate volume, digital rectal exam results, PSA derivative data, or pathology results (including Gleason score).
  • the models learn to recognize outliers in the data set and so give such outlying data less weight. Combinations of biomarkers, therefore, minimize the impact of outlying data for one or a small subset of biomarkers.
  • prognostic ANN are trained in the same manner as diagnostic ANN, but the input data, optionally normalized or scaled, is for one or more of the secreted protein biomarkers SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164.
  • training may optionally further comprise inclusion of data for one or more of PSA, %fPSA, PSA doubling time, PSA velocity, PSA recurrence, prostate volume, digital rectal exam results, PSA derivative data, or pathology results (including Gleason score).
  • the disclosure also provides a computer-implemented method for prognosing prostate cancer comprising: identifying one or more of SPOCK, PDGFD, CHGA, CAV1 , RLN 1 , IGFBP7, BGN,
  • each of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN, IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164 is identified as a parameter.
  • the disclosure provides a computer readable medium including computer code for causing a processor to perform the steps of: identifying one or more of SPOCK, PDGFD, CHGA, CAV1 , RLN1 , IGFBP7, BGN,
  • IL6, VEGF, LTF, FMOD, AGR2, SERPINA3, AZGP1 , FAM3B, and CD164 as parameters; receiving initial data values for the identified parameters from a patient with a known disease status; training an artificial neural network using the parameters and received initial data; modifying a template using learning gained by the artificial neural network; and using the modified template to prognose a new patient based on new input values.
  • Trained ANN models are tested by asking whether the model can correctly predict the clinical outcome using patient data other than that with which the ANN model was trained, but having a known clinical outcome.
  • the model output from 0 (control or moderate risk) to 1 (cancer or high risk) can be calculated in blind fashion by the average error of all N predictions (a validation group).
  • the receiver operating characteristic (ROC) curve can be built to calculate the outcome of clinical prediction: specificity and sensitivity of prostate cancer.
  • the invention encompasses each intervening value between the upper and lower limits of the range to at least a tenth of the lower limit's unit, unless the context clearly indicates otherwise. Further, the invention encompasses any other stated intervening values. Moreover, the invention also encompasses ranges excluding either or both of the upper and lower limits of the range, unless specifically excluded from the stated range.
  • Biofluids are complex mixtures of proteins. It is therefore difficult to discover biomarker candidates using a biofluid as the starting material.
  • proteins encoded by genes that we have previously identified as having an expression signature in prostate tumor tissue that varied from that in benign matched tissue using an epithelial cell transcriptome from 50 matched pairs of laser capture micro-dissected benign and malignant prostate epithelial cells. See copending application no. PCT/US05/15926, incorporated herein by reference.
  • a unique panel of secreted proteins having altered expression in prostate tumor cells as compared to benign prostate cells were selected as biomarkers for diagnosing prostate cancer.
  • Table 1 presents those secreted proteins selected as diagnostic biomarkers for prostate cancer: Table 1 :
  • a unique panel of secreted proteins that are prognostic biomarkers for prostate cancer was also selected. Alterations in the expression patterns of these proteins distinguish prostate tumor cells from benign prostate cells when comparing moderate risk prostate cancer samples to high risk prostate cancer samples.
  • Table 2 presents those secreted proteins selected as prognostic biomarkers for prostate cancer: Table 2:
  • the prognostic panel includes proteins encoded by genes that are differentially expressed in tumors of patients with moderate risk or high risk prostate cancer or who have increased risk for cancer recurrence following radical prostatectomy.
  • Figure 1 shows a meta-analysis of gene expression data for the seven most frequently upregulated genes in the diagnostic panel.
  • the individual discriminatory power of the seven most frequently up-regulated genes between normal and prostate tissue is presented in box-plot format, and includes both a GeneChip ® analysis (Affymetrix, Santa Clara, Ca), and an analysis of data extracted from the OncomineTM database (Compendia Bioscience, Ann Arbor, Mi). Examination of any of these genes resulted in the ability to separate normal tissue from prostate cancer tissue (p ⁇ 0.05).
  • the secreted proteins listed in Table 1 and Table 2 are present and can be detected in the biofluids of patients.
  • a direct ELISA we detected expression of SPOCK, F5, NPY, CRISP3, PLA2G7, and TMEFF2 protein in serum pooled from controls, patients with prostate cancer (CaP), and patients with metastatic prostate cancer (Met) ( Figure 2).
  • Appropriate antibody pairs for the capture and detection of the remaining secreted biomarkers can be developed and validated using routine experimentation.
  • direct- or sandwich- ELISA we have confirmed overexpression of SPOCK, PLA2G7, NPY, CRISP3 and F5, protein in serum or plasma of prostate cancer versus control.
  • PSA prostate cancer
  • serum PSA is also frequently elevated in non-malignant conditions and, in practice, only about 25% of men with elevated serum PSA have prostate cancer on tissue biopsy.
  • PSA is a very sensitive assay, its specificity is somewhat lacking.
  • SPOCK1 and PLA2G7 serum levels were quantitatively measured by ELISA.
  • Figure 3A and 3B show that both SPOCK1 (Fig. 3A) and PLA2G7 (Fig. 3B) can successfully distinguish the prostate cancer (CaP) cohort from the control cohort. The results for each were statistically significant (p ⁇ 0.05).
  • PLA2G7 is superior to total PSA in separating the prostate cancer and control cohorts. (Compare the sensitivity cutoffs for PLA2G7 and for tPSA.) The separating effect became even greater when PLA2G7 is combined as a panel with tPSA in terms of AUC for both subgroups.
  • use of the ANN algorithm improved specificity compared to the SVM algorithm in both groups for either sensitivity cutoff.
  • both SMOC1 and F5 separate the biopsy positive (prostate cancer) group from the biopsy negative (control) group (p ⁇ 0.05 for both SMOC1 and F5 using Student t- test).
  • SMOC1 correctly distinguished 7 of 15 biopsy positive samples and 6 of 8 biopsy negative samples.
  • F5 distinguished the biopsy positive cohort from the negative cohort with 40% sensitivity and 87% specificity.
  • serum PSA levels for two cohorts were similar at their median values (Fig. 6C).
  • a panel including serum PSA and post-DRE urine SMOC1 and F5 data showed combined sensitivity and specificity of 87% and 87%, respectively.
  • specificity of a panel SMOC1 and F5
  • PSA specificity remains at 25%.
  • SMOC1 and F5 either individually or in combination, should also enhance the specificity of PSA.
  • a clinical test should detect prostate cancer with high specificity and sensitivity.
  • biomarkers By combining individual biomarkers into a panel, it is possible to improve diagnostic power compared to single biomarkers.
  • Table 1 data for the up-regulated genes presented in Table 1.
  • Figure 7 When we calculated the probability of prostate diagnosis based on the exhaustive combination of these seven genes, we found that the probability of prostate cancer linearly correlated with the frequency of up-regulated genes encoding secretory proteins (linearity constant at 0.9632) (Figure 7). Combining increasing numbers of the prostate cancer overexpressed genes resulted in an increased association with prostate cancer specimens in our tumor versus benign prostate epithelial cell data set (Figure 8).
  • the pie charts illustrate patient distribution by tumor versus benign gene expression ratios for PLA2G7, F5, TMEFF2, SMOC, NPY, SPOCK, and CRISP3. When all seven genes encoding for secretory proteins were combined, these genes exhibited greater than 70% association with prostate cancer.
  • the ANN model is then "trained.” Data for all but one patient of a data set of N patients with different marker levels are used in the training, then a prediction is made for the remaining patient in the basis of N-1 classifiers. This is referred to as the 'leave-one-out' method. (Stephan et al., (2006) PROSTATE 66: 651-59.) To avoid overfitting, Bayesian regularization within the training run developed by Finne et al. ((2000) UROLOGY 56: 418-22) is used. After training the ANN models, the model output from 0 (control or moderate risk) to 1 (cancer or high risk) is calculated in blind fashion by the average error of all N predictions (a validation group).
  • the receiver operating characteristic (ROC) curve is built to calculate the outcome of clinical prediction: specificity and sensitivity of prostate cancer.
  • the area under the ROC curves are calculated and compared using in-house user-defined M-file scripts within the MATLAB software package. Changing clinical factors further optimizes the performance of ANN models.
  • Control sera are used to develop diagnostic ANN models.
  • the control sera are from men having serum PSA ⁇ 2 ng/ml, normal PSA velocity (if data is available), normal digital rectal examination (DRE); no genitourinary symptoms, and optionally a biopsy that is negative for BPH or cancer.
  • men are age and race matched to the BPH and cancer groups.
  • the BPH group includes patients having LUTS (lower urinary track symptoms), a normal DRE, a biopsy that is negative for cancer, and a PSA of 2-10 ng/ml).
  • the prostate cancer group includes patients with a biopsy that was positive for cancer and a serum PSA of 2-10 ng/ml.
  • the prostate cancer patients are grouped into those with biologically aggressive disease (high risk, Gleason Score of 7 or greater) and those with low/moderately aggressive disease (moderate risk, Gleason Score of 6 or less) based on tumor pathology. Patients are also stratified for disease recurrence (biochemical recurrence by rising PSA after radical prostectomy (RP) and/or clinical metastasis) and recurrence free survival after RP for the evaluation of prognostic markers characterizing disease progression or progression free survival.
  • RP radical prostectomy
  • F5 recurrence free survival after RP for the evaluation of prognostic markers characterizing disease progression or progression free survival.

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Abstract

La présente invention concerne des biomarqueurs de protéine sécrétés pour le cancer de la prostate, des kits de diagnostic et de pronostic comportant des réactifs qui se lient aux biomarqueurs de protéine sécrétés, et des procédés et des systèmes pour utiliser ces biomarqueurs afin de diagnostiquer et de pronostiquer le cancer de la prostate.
PCT/US2007/081792 2006-10-19 2007-10-18 Procédés, kits et systèmes pour diagnostiquer et pronostiquer le cancer de la prostate en utilisant des biomarqueurs sécrétés WO2008067065A2 (fr)

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