Discriminatory Mechanisms in Early-Onset and Lethal Prostate Cancer

常规线粒体功能的重编程是癌症发生和前列腺增生的关键组成部分。 癌症的侵略性我们假设，早发性和致死性的关键区别机制， 前列腺癌是通过在早期发育和年轻成人生活中暴露于环境而发生的， 重新编程线粒体功能，导致或使早发性和致命的前列腺癌。 理性与创新。虽然机制不能通过回顾性分析来证明，但我们可以获得 在前列腺癌发病前几年收集的年轻男性（中位年龄34岁）的储存库样本， 围概念的父亲和母亲怀孕储存库样本的男性谁后来开发早期- 发病前列腺癌，使我们能够应用强大的分析能力， 结果与并发的前瞻性暴露措施。这造成了前所未有的 有机会检验核心假设，即在早期发育中暴露于内分泌干扰物， 与线粒体重编程的代谢特征有关， 随后的早发性（<60岁）和致死性前列腺癌。如果正确的话，这些发现将为 加强保护途径和阻断风险途径的预防战略。 设计研究人群是儿童健康和发展研究的60岁两代随访 （CHDS）队列，20世纪60年代加利福尼亚州阿拉米达县的一个独特的代表性样本， 美国人口。这种设计使我们能够解决风险的差异。目标1是全代谢组 相关性研究（MWAS），以检验以下假设： 年轻成年男性诊断血清可预测非裔美国人和非裔美国人随后发生的致死性前列腺癌 非裔美国人在CHDS父亲的一代。Aim 2是一项全暴露体关联研究（ExWAS） 为了检验年轻成年男性的诊断前血清含有内分泌干扰化学物质的假设， 与CHDS父亲的非裔美国人和非裔美国人的致命前列腺癌相关 一代目的3：用父亲围产期血清和母亲妊娠血清检测代谢性 特征和环境暴露预测CHDS儿子一代早发性前列腺癌。 这项研究将通过以种族特异性的方式显示线粒体是否 代谢途径在癌症发作前几十年随着早发和致死性前列腺癌风险而变化， 这些变化是否与同时发生的环境暴露有关， 代谢或环境暴露与早发性前列腺癌之间存在关联。研究 有可能区分生命过程中预防最有效的时间。结果将有助于 确定将受益于密集筛查的男性，并加速预防， 非裔美国人谁有不可接受的高风险早发性和致命的前列腺癌。

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.