Project 1: Molecular Predictors of Prostate Cancer Progression and Mortality

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PROJECT SUMMARY/ABSTRACT Prostate cancer (PC) is a major cause of cancer-related morbidity and mortality. Prostate-specific antigen (PSA) screening is controversial, and current consideration of high-risk men is inadequate. Additionally, clinicopathological criteria are insufficient to differentiate indolent versus aggressive disease. The recent discovery of a high prevalence of high-to-moderate penetrance germline cancer risk mutations in metastatic PC (mPC) will lead to increased genetic testing and cascade testing of unaffected male relatives, thus identifying men at high risk for developing aggressive PC. Preliminary evidence suggests the need for refined cancer screening in this high-risk group. The overall intent of this project is to find men with germline mutations of interest, both those with mPC as well as their male first-degree relatives who are at high risk for aggressive PC. We seek to further characterize PC in the context of germline DNA repair gene (gDRG) defects using evaluation of clinical, pathologic and molecular features, including targeted next generation sequencing methods; to recruit at-risk male first-degree relatives through cascade genetic testing; and to offer a novel PC early detection clinical trial incorporating novel biomarkers, including age-adjusted PSA thresholds, imaging, novel urine biomarkers and the tumor prognostic biomarkers we discovered and validated in the past grant period, and to further understand the crucial process of cascade genetic testing that will be required for optimal outcomes. The proposed aims are: Specific Aim 1: Determine clinical, pathologic and molecular predictors of gDRG mutation carriers among men with mPC. Specific Aim 2: Conduct an early detection study for male gDRG mutation carriers at high risk for mPC. Specific Aim 3: Characterize the stepwise cascade genetic testing process from index cases to their at risk first-degree relatives (FDRs). This effort builds upon our current population-based SPORE work focused on finding and validating novel prognostic biomarkers for aggressive PC (e.g., tumor DNA methylation and mRNA expression biomarkers for distinguishing men at high risk for metastatic progression and PC-specific mortality) and transitions towards a more direct clinical applicability. We believe our approach will be of high interest and relevance to men with mPC and gDRG, and their sons and brothers who may be at increased risk for mPC due to carrying the same gDRG mutation. At present, no unified PC early detection recommendations exist for men at increased PC risk defined by inherited gDRG mutations. Our PC early detection clinical study will use established and novel minimally invasive biomarkers with a goal of changing the standard of care for this high-risk group.