Prostate cancer (PCa) is the most common solid tumor in men and is a major cause of cancer-related morbidity and mortality. Prostate-specific antigen (PSA) testing has increased the number of men diagnosed with PCa, but -30-42% of these patients have indolent tumors that carry a low probability for progression to clinically significant PCa. Clinicopathological criteria alone are not always adequate for predicting which tumors will remain indolent vs become aggressive, so many patients are over-treated and some are undertreated. Thus, biomarkers to distinguish men with less vs more aggressive disease are urgently needed. Both inherited genetic variation (e.g., SNPs) and tumor epigenomic aberrations (e.g., DNA hypermethylation) likely contribute to PCa aggressiveness. Preliminary evidence supports both mechanisms, which may alter host-tumor immunity, tumor growth rate, or metastatic propensity. The overall intent of this population sciences research is to validate genetic-epigenetic biomarkers for aggressive PCa that can be translated into clinical use. Toward this goal, the project has the following aims: 1) To complete validation of a panel of 30 PCSM-associated SNPs in two independent PCa patient cohorts;2) To characterize genome-wide DNA methylation (450K CpG sites) profiles in prostate tumor tissue in association with PCa-specific outcomes (e.g., recurrence, metastasis, PCSM);and, 3) To test validated PCSM-associated SNPs (Aim 1) and top-ranked differentially methylated genes (Aim 2) as an integrated panel of prognostic biomarkers for distinguishing clinically localized aggressive PCa. The proposed plan builds on our prior SPORE work, taking advantage of a population-based PCa cohort with germline DNA, tumor tissue, clinical and PCa-specific outcomes data, as well as other PCa cohorts with available DNA and outcomes data. Univariate, stratified, and multivariate analyses will be completed to evaluate PCSM-associated SNPs and top-ranked differentially methylated genes associated with aggressive PCa for potential clinical utility. The Cox proportional hazards model will be used to calculate hazard ratios, 95% CIs, and p-values to examine the association of individual and combinations of germline genetic and somatic (DNA methylation) biomarkers with PCa outcomes. The overall goal is to identify and validate prognostic genetic-epigenetic biomarkers that will translate into better patient management and outcomes as well as to identify new molecular targets that may lead to novel therapies or prevention approaches for PCa.

Public Health Relevance

Prostate cancer (PCa) is a major cause of mortality, but it is not currently possible to accurately predict which tumors will remain indolent vs become life-threatening. To identify prognostic biomarkers, the proposed study will utilize samples and data from a population-based cohort of 1,458 PCa patients to assess genome-wide DNA methylation in tumor tissue and germline single nucleotide variants in candidate genes in relation to recurrence and PCa-specific mortality. Our goal is to identify and validate prognostic genetic-epigenetic biomarkers that will translate into better patient management and outcomes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-M (M1))
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Hruszkewycz, Andrew M
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Fred Hutchinson Cancer Research Center
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Viswanathan, Srinivas R; Ha, Gavin; Hoff, Andreas M et al. (2018) Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing. Cell 174:433-447.e19
Armenia, Joshua; Wankowicz, Stephanie A M; Liu, David et al. (2018) The long tail of oncogenic drivers in prostate cancer. Nat Genet 50:645-651
Plymate, Stephen R; Sharp, Adam; de Bono, Johann S (2018) Nuclear Circulating Tumor Cell Androgen Receptor Variant 7 in Castration-Resistant Prostate Cancer: The Devil Is in the Detail. JAMA Oncol 4:1187-1188
Russo, Joshua W; Gao, Ce; Bhasin, Swati S et al. (2018) Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer. Cancer Res 78:6354-6362
Sowalsky, Adam G; Ye, Huihui; Bhasin, Manoj et al. (2018) Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations. Cancer Res 78:4716-4730
Zhu, Yezi; Sharp, Adam; Anderson, Courtney M et al. (2018) Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Eur Urol 73:727-735
Chalfin, Heather J; Glavaris, Stephanie A; Malihi, Paymaneh D et al. (2018) Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms. J Urol 199:1494-1501
Inoue, Lurdes Y T; Lin, Daniel W; Newcomb, Lisa F et al. (2018) Comparative Analysis of Biopsy Upgrading in Four Prostate Cancer Active Surveillance Cohorts. Ann Intern Med 168:1-9
Cheng, Heather H; Plets, Melissa; Li, Hongli et al. (2018) Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone-sensitive prostate cancer. Prostate 78:121-127
Levesque, Christine; Nelson, Peter S (2018) Cellular Constituents of the Prostate Stroma: Key Contributors to Prostate Cancer Progression and Therapy Resistance. Cold Spring Harb Perspect Med 8:

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