Discriminatory Mechanisms in Early-Onset and Lethal Prostate Cancer

传统线粒体功能的重新编程是致癌和前列腺癌的关键组成部分 癌症侵袭性。我们假设早发性和致死性疾病的主要区别机制 前列腺癌是通过在发育早期和青年时期暴露在环境中而发生的 重新编程线粒体功能，导致或导致早发性和致命性前列腺癌。 理论基础和创新。虽然机制不能通过回顾分析来证明，但我们可以访问 在前列腺癌发病前的年轻男性(中位年龄34岁)中收集的储存库样本，以及 为后来早期发育的男性提供的围产期父亲和母亲怀孕储存库样本- 前列腺癌的发病，使我们能够应用强大的分析能力将预测的代谢信号联系起来 对结果进行评估，同时进行前瞻性暴露测量。这创造了一个前所未有的 检验核心假设的机会，即在发育早期暴露内分泌干扰 和年轻的成年期与线粒体重新编程的代谢特征和 随后早发(60岁)和致命性前列腺癌。如果正确，研究结果将提供一个基础 用于加强保护途径和阻断风险途径的预防战略。 设计。研究人群是对儿童健康和发育研究的两代60岁的跟踪调查 (CHDS)队列，20世纪60年代加州阿拉米达县的一个独特的代表性样本，S有相当大的非洲人 美国人口。这种设计使我们能够解决风险方面的差异。目标1是整个代谢组的 关联研究(MWAS)，以检验假设线粒体相关的代谢特征在前 年轻成年男性的诊断血清预测非裔美国人和非美国人随后的致命性前列腺癌 CHDS父亲那一代的非裔美国人。AIM 2是一项Exposome-wide Association研究(Exwas) 为了验证年轻成年男性诊断前血清中含有干扰内分泌的化学物质的假设 CHDS父亲的非洲裔美国人和非非洲裔美国人与致命性前列腺癌相关 一代。目的3使用父亲的围产期血清和母亲的妊娠血清来测试代谢 签名和环境暴露预测先天先天前列腺癌的发生。 这项研究将产生持续的影响，以种族特有的方式展示线粒体 新陈代谢途径随着癌症发病前几十年的早发性和致命性前列腺癌风险而变化。 这些变化是否与同时的环境暴露有关，以及是否存在多代人 代谢或环境暴露与早发性前列腺癌之间存在关联。这项研究 有可能区分生命过程中预防最有效的时间。结果将有所帮助 确定哪些男性将从密集筛查中受益，并加快预防工作，这与 非洲裔美国人罹患早发性和致命性前列腺癌的风险高得令人无法接受。

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.