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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097186-12
Application #
8933573
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Program Officer
Hruszkewycz, Andrew M
Project Start
2002-09-19
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
$197,023
Indirect Cost
$75,847
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Barnard, Monique; Quanson, Jonathan L; Mostaghel, Elahe et al. (2018) 11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer. J Steroid Biochem Mol Biol 183:192-201
Ganaie, Arsheed A; Beigh, Firdous H; Astone, Matteo et al. (2018) BMI1 Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models. Clin Cancer Res 24:6421-6432
Schweizer, Michael T; Haugk, Kathleen; McKiernan, Jožefa S et al. (2018) A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer. PLoS One 13:e0198389
Peacock, James W; Takeuchi, Ario; Hayashi, Norihiro et al. (2018) SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1. EMBO Mol Med 10:219-238
Pollan, Sara G; Huang, Fangjin; Sperger, Jamie M et al. (2018) Regulation of inside-out ?1-integrin activation by CDCP1. Oncogene 37:2817-2836
Wu, Yi-Mi; Cie?lik, Marcin; Lonigro, Robert J et al. (2018) Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 173:1770-1782.e14
Schweizer, Michael T; Hancock, Michael L; Getzenberg, Robert H et al. (2018) Hormone levels following surgical and medical castration: defining optimal androgen suppression. Asian J Androl 20:405-406
Yan, Qingxiang; Bantis, Leonidas E; Stanford, Janet L et al. (2018) Combining multiple biomarkers linearly to maximize the partial area under the ROC curve. Stat Med 37:627-642
Lam, Hung-Ming; Nguyen, Holly M; Corey, Eva (2018) Generation of Prostate Cancer Patient-Derived Xenografts to Investigate Mechanisms of Novel Treatments and Treatment Resistance. Methods Mol Biol 1786:1-27
Lam, Hung-Ming; Corey, Eva (2018) Supraphysiological Testosterone Therapy as Treatment for Castration-Resistant Prostate Cancer. Front Oncol 8:167

Showing the most recent 10 out of 400 publications