Germline Genetics and Risk of Prostate Cancer in Diverse Populations from the All of Us Program

“我们所有人”计划中不同人群的种系遗传学和前列腺癌风险

• 批准号: 10798864
• 负责人: Burcu Frances Darst
• 金额: $ 19.26万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798864
• 关键词: African; African American; African ancestry; All of Us Research Program; Asian population; BRCA2 gene; CHEK2 gene; Cancer Etiology; Candidate Disease Gene; Categories; Cessation of life; Complex; Data; Disease; Disparity; East Asian; Economics; Education; European; European ancestry; Genes; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genotype; Goals; Healthcare; Heritability; Hispanic Populations; Incidence; Indolent; Inherited; Investigation; Knowledge; Life Style; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Modeling; Obesity; Outcome; PALB2 gene; Pathogenicity; Population; Population Heterogeneity; Preventive measure; Relative Risks; Reporting; Research; Resources; Risk; Risk Factors; Sample Size; Screening for Prostate Cancer; Smoking Status; Socioeconomic Factors; Variant; carrier status; cost; exome; genetic risk factor; genetic variant; genome sequencing; genome-wide; health care availability; health disparity; healthy lifestyle; high risk men; improved; lifestyle factors; man; men; modifiable risk; mortality; non-genetic; novel; polygenic risk score; prostate cancer prevention; prostate cancer risk; rare variant; risk variant; screening; social; unhealthy lifestyle; whole genome

PROJECT SUMMARY Prostate cancer is the second most common cancer and the second leading cause of cancer death in US men, with African American men having the highest incidence and mortality rates. Prostate cancer is strongly influenced by genetic factors, and polygenic risk scores (PRS) of common genetic variants are highly predictive of prostate cancer risk in men from European, African, East Asian, and Hispanic populations. Rare pathogenic variants also contribute to overall and aggressive prostate cancer risk, with 15% of metastatic cases carrying such variation. However, due to high sequencing costs, our knowledge of the contribution of rare genetic variation to prostate cancer risk is largely based on candidate gene studies, with of the few whole-exome or whole-genome studies conducted to date having sample sizes that are large enough for the discovery of novel rare variants/genes. Further, the majority of men included in common and rare genetic variant investigations of prostate cancer risk have been from European ancestry populations, limiting our knowledge on genetic risk of prostate cancer in other populations. The objective of this research is to elucidate genetic factors that contribute to risk of overall and aggressive prostate cancer across diverse populations and how such factors can be combined with lifestyle, environmental, and socioeconomic factors to more accurately characterize risk of prostate cancer. In Aim 1, we will investigate the contribution of rare and common genetic variants to prostate cancer risk across diverse populations, with the goal of validating known genetic risk factors and discovering novel genetic risk regions. In Aim 2, we will investigate whether genetic risk of prostate cancer, as measured by a PRS of known common genetic risk variants, can be modified by rare pathogenic variant carrier status, lifestyle factors, and socioeconomic factors across diverse populations. This research will be conducted in the All of Us Research Program, combining results from Aim 1 with other large-scale investigations to improve our ability to identify novel genetic risk regions. Findings from this investigation are expected to identify novel mechanisms novel mechanisms to target for preventative measures and improve our understanding of the complex interplay of genetic risk and modifiable risk factors of prostate cancer. Further, this investigation is anticipated to improve our ability to identify men at increased risk of overall and aggressive prostate cancer, which could have important screening and healthcare implications for prostate cancer prevention.

项目概要 前列腺癌是美国男性中第二常见的癌症，也是导致癌症死亡的第二大原因， 其中非洲裔美国男性的发病率和死亡率最高。前列腺癌的发病率非常高 受遗传因素影响，常见遗传变异的多基因风险评分（PRS）具有很强的预测性 欧洲、非洲、东亚和西班牙裔男性患前列腺癌的风险。罕见致病性 变异也会增加总体和侵袭性前列腺癌风险，15% 的转移病例携带 这样的变化。然而，由于高昂的测序成本，我们对罕见遗传变异的贡献的了解 前列腺癌风险很大程度上基于候选基因研究，其中包括少数全外显子组或全基因组研究 迄今为止进行的研究样本量足够大，足以发现新的稀有物质 变体/基因。此外，大多数男性都参与了常见和罕见的遗传变异研究 前列腺癌风险来自欧洲血统人群，限制了我们对前列腺癌遗传风险的了解 其他人群的前列腺癌。本研究的目的是阐明影响遗传因素 不同人群患整体性和侵袭性前列腺癌的风险以及这些因素如何影响 结合生活方式、环境和社会经济因素，更准确地描述风险 前列腺癌。在目标 1 中，我们将研究罕见和常见的遗传变异对前列腺的影响 不同人群的癌症风险，目的是验证已知的遗传风险因素并发现 新的遗传风险区域。在目标 2 中，我们将调查前列腺癌的遗传风险（通过测量） 已知常见遗传风险变异的 PRS，可以通过罕见致病变异携带者状态、生活方式进行修改 因素以及不同人群的社会经济因素。这项研究将在我们所有人中进行 研究计划，将目标 1 的结果与其他大规模调查相结合，以提高我们的能力 识别新的遗传风险区域。这项调查的结果预计将确定新的机制 以预防措施为目标并提高我们对复杂相互作用的理解的新机制 前列腺癌的遗传风险和可改变的危险因素。此外，这项调查预计将改善 我们有能力识别总体和侵袭性前列腺癌风险增加的男性，这可能具有重要意义 筛查和医疗保健对预防前列腺癌的影响。