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 under-treated. 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.
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.
|Kuo, Kevin F; Hunter-Merrill, Rachel; Gulati, Roman et al. (2015) Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer. Clin Genitourin Cancer 13:6-Oct|
|True, Lawrence D (2014) Methodological requirements for valid tissue-based biomarker studies that can be used in clinical practice. Virchows Arch 464:257-63|
|Lam, Hung-Ming; Vessella, Robert L; Morrissey, Colm (2014) The role of the microenvironment-dormant prostate disseminated tumor cells in the bone marrow. Drug Discov Today Technol 11:41-7|
|Montgomery, Bruce; Cheng, Heather H; Drechsler, James et al. (2014) Glucocorticoids and prostate cancer treatment: friend or foe? Asian J Androl 16:354-8|
|Sprenger, Cynthia C T; Plymate, Stephen R (2014) The link between androgen receptor splice variants and castration-resistant prostate cancer. Horm Cancer 5:207-17|
|Tarnow, Carolin; Engels, Géraldine; Arendt, Annika et al. (2014) TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J Virol 88:4744-51|
|O'Hurley, Gillian; Prencipe, Maria; Lundon, Dara et al. (2014) The analysis of serum response factor expression in bone and soft tissue prostate cancer metastases. Prostate 74:306-13|
|Barnett, Christine M; Heinrich, Michael C; Lim, Jeong et al. (2014) Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer. Clin Cancer Res 20:1306-12|
|Mostaghel, Elahe A; Plymate, Stephen R; Montgomery, Bruce (2014) Molecular pathways: targeting resistance in the androgen receptor for therapeutic benefit. Clin Cancer Res 20:791-8|
|Chéry, Lisly; Lam, Hung-Ming; Coleman, Ilsa et al. (2014) Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget 5:9939-51|
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