Discriminatory Mechanisms in Early-Onset and Lethal Prostate Cancer

Reprogramming of conventional mitochondrial function is a key component of carcinogenesis and prostate cancer aggressiveness. We hypothesize that key discriminatory mechanisms in early-onset and lethal prostate cancer occur through environmental exposures in early development and in young adult life which reprogram mitochondrial function, causing or enabling early-onset and fatal prostate cancer. Rationale and Innovation. While mechanisms cannot be proven by retrospective analyses, our access to repository samples collected in young men (median age 34) years before prostate cancer onset, and also peri-conceptual paternal and maternal pregnancy repository samples for men who later developed early- onset prostate cancer, enable us to apply powerful analytical capabilities to link predictive metabolic signatures of outcome with concurrent prospective measures of exposures. This creates an unprecedented opportunity to test the central hypothesis that endocrine-disrupting exposures in early development and young adulthood are associated with metabolic signatures of mitochondrial reprogramming and subsequent early-onset (< age 60) and lethal prostate cancer. If correct, findings will provide a foundation for prevention strategies to augment protective pathways and block risk pathways. Design. The study population is a 60 y two-generation follow-up of the Child Health and Development Studies (CHDS) cohort, a unique representative sample of Alameda County CA in the 1960’s with a sizeable African American population. This design allows us to address disparities in risk. Aim 1 is a Metabolome-Wide Association Study (MWAS) to test the hypothesis that mitochondria-associated metabolic signatures in pre- diagnostic serum of young adult men predict subsequent lethal prostate cancer in African American and non- African Americans in the CHDS father’s generation. Aim 2 is an Exposome-Wide Association Study (ExWAS) to test the hypothesis that pre-diagnostic serum of young adult men contain endocrine-disrupting chemicals associated with lethal prostate cancer in African Americans and non-African Americans in the CHDS father’s generation. Aim 3 uses paternal peri-conceptual serum and maternal pregnancy serum to test for metabolic signatures and environmental exposures that predict early-onset prostate cancer in CHDS sons’ generation. This research will have sustained impact by showing, in a race-specific manner, whether mitochondrial metabolic pathways vary with early-onset and lethal prostate cancer risk decades before cancer onset, whether these changes associate with concurrent environmental exposures, and whether multi-generational associations occur between metabolic or environmental exposures and early-onset prostate cancer. The study has the potential to distinguish the time in the life-course when prevention is most effective. Results will help define men who will benefit from intense screening and accelerate prevention with critical relevance to African Americans who have unacceptably high risk of early-onset and lethal prostate cancer.