Discriminatory Mechanisms in Early-Onset and Lethal Prostate Cancer

早发性和致命性前列腺癌的歧视机制

• 批准号: 10674785
• 负责人: BARBARA A COHN
• 金额: $ 24.6万
• 依托单位: PUBLIC HEALTH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-13 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674785
• 关键词: Acceleration; Address; African American; African American population; Age; Alcohol consumption; Bioenergetics; Birth; Blood specimen; Cessation of life; Child Development; Child Health; Cohort Studies; County; Daughter; Development; Diagnostic; Disparity; Endocrine Disruptors; Endocrine disruption; Environmental Exposure; Environmental Risk Factor; Fathers; Foundations; Generations; Income; Life; Life Cycle Stages; Link; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metabolic; Metabolic Pathway; Mitochondria; Mothers; Occupations; Onset of illness; Outcome; Pathway interactions; Pregnancy; Prevention; Prevention strategy; Race; Research; Resolution; Risk; Sampling; Serum; Son; Testing; Time; cancer diagnosis; cancer health disparity; carcinogenesis; chemical association; cigarette smoking; design; early onset; environmental chemical; follow-up; health disparity; high risk; innovation; male; malignant breast neoplasm; men; metabolome; metabolomics; mortality; prenatal; programs; prospective; prostate cancer risk; protective pathway; racial disparity; repository; screening; sex; study population; young adult; young man

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.

再编程常规线粒体功能是致癌和前列腺的关键组成部分 癌症的侵略性。我们假设早期发作和致命的关键歧视机制 前列腺癌通过早期发展和成年生活中的环境暴露而发生 重编程线粒体功能，导致或引起早期发作和致命的前列腺癌。 理由和创新。虽然无法通过回顾性分析来证明机制，但我们对 前列腺癌发作前的年轻男性（中位年龄）收集的存储库样本，也是 男性的孕妇外孕期和孕妇妊娠库样本 发作前列腺癌，使我们能够应用强大的分析能力来链接预测代谢特征 结局以及同时预期的暴露措施。这创造了前所未有的 检验中心假设的机会，即内分泌中断的暴露在早期发展中 成年和成年与线粒体重编程和 随后的早期发作（<60岁）和致命的前列腺癌。如果正确，发现将为基础提供基础 用于预防策略，以增加受保护的途径并阻止风险途径。 设计。研究人群是儿童健康与发展研究的60 y两代随访 （CHDS）同类，1960年代阿拉米达县的独特代表样本，具有相当大的非洲人 美国人口。这种设计使我们能够解决风险分配。 AIM 1是全代谢组 协会研究（MWAS）检验了以下假设：线粒体相关的代谢特征 年轻男性的诊断血清预测非裔美国人和非美国的致命前列腺癌随后 冠心病父亲的非洲裔美国人。 AIM 2是一项全面的社会研究（EXWAS） 为了检验以下假设，即年轻成年男性诊断前血清中含有内分泌干扰化学物质 与非洲裔美国人和非洲美国人的致命前列腺癌有关 一代。 AIM 3使用父亲概念血清和孕妇妊娠血清来测试代谢 预测CHDS儿子一代早期发作的前列腺癌的特征和环境暴露。 这项研究将通过以种族特定的方式显示线粒体的持续影响 代谢途径在癌症发作前几十年随早期发病和致命的前列腺癌风险而变化， 这些变化是否与并发环境暴露以及多代 代谢或环境暴露与早期发作的前列腺癌之间发生关联。研究 在预防最有效时，有可能区分生命过程中的时间。结果将有所帮助 定义将受益于强烈筛查和加速预防的男人，并与 早期发作和致命前列腺癌风险高的非裔美国人。