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: 10306223
• 负责人: BARBARA A COHN
• 金额: $ 49.13万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306223
• 关键词: Address; African American; Age; Alcohol consumption; Bioenergetics; Birth; Blood specimen; Cessation of life; Child Development; Child Health; Cohort Studies; County; Daughter; Development; Diagnostic; 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; Population; Pregnancy; Prevention; Prevention strategy; Race; Research; Resolution; Risk; Sampling; Serum; Son; Testing; Time; cancer diagnosis; cancer health disparity; carcinogenesis; case control; cigarette smoking; design; early onset; environmental chemical; follow-up; health disparity; high risk; innovation; male; malignant breast neoplasm; men; metabolome; metabolomics; mortality; prenatal; prospective; prostate cancer risk; 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.

传统线粒体功能的重编程是致癌和前列腺癌的关键组成部分 我们与早发型和致命性的关键歧视机制作斗争。 前列腺癌是通过早期发育和年轻成人生活中的环境暴露而发生的 重新编程线粒体功能，导致或促成早发性和致命性前列腺癌。 基本原理和创新。虽然机制无法通过回顾性分析来证明，但我们可以利用 在前列腺癌发病前几年收集的年轻男性（中位年龄 34）的储存库样本，以及 围孕期父亲和母亲怀孕储存库样本，用于后来发展为早期发育的男性 发病的癌症，使我们能够应用强大的前列腺分析能力来链接预测代谢特征 结果与同时的前瞻性暴露测量这创造了前所未有的结果。 有机会检验早期发育过程中内分泌干扰暴露这一中心假设 成年早期与线粒体重编程的代谢特征有关 如果正确的话，研究结果将提供基础。 制定预防策略，以增强保护途径并阻断风险途径。 设计研究人群是儿童健康与发展研究的 60 岁两代人。 (CHDS) 队列，是 1960 年代加利福尼亚州阿拉米达县的一个独特的代表性样本，其中有相当多的非洲人 美国人口。这一设计使我们能够解决风险差异问题。目标 1 是代谢组范围内的风险。 关联研究 (MWAS) 检验线粒体相关代谢特征在预 年轻成年男性的诊断血清可预测非洲裔美国人和非裔美国人随后致命的前列腺癌 CHDS 父亲一代的非裔美国人目标 2 是一项全暴露组关联研究 (ExWAS)。 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非裔美国人的致命性前列腺癌相关 目标 3 使用父亲围孕血清和母亲妊娠血清来测试代谢。 预测 CHDS 儿子一代早发性前列腺癌的特征和环境暴露。 这项研究将以特定种族的方式显示线粒体是否 代谢途径随癌症发病前数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发生的环境暴露有关，以及多代人是否 代谢或环境暴露与早发性前列腺癌之间存在关联。 有可能区分生命历程中预防最有效的时间。结果将有所帮助。 定义将受益于严格筛查并加速预防的男性，这与以下方面至关重要 非裔美国人患早发性和致命性前列腺癌的风险高得令人无法接受。