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

项目总结 前列腺癌是美国男性第二常见的癌症，也是癌症死亡的第二大原因。 其中非洲裔美国人的发病率和死亡率最高。前列腺癌是一种强烈的 受遗传因素的影响，常见遗传变异的多基因风险分数(PR)具有很高的预测性 欧洲、非洲、东亚和西班牙裔人群中前列腺癌风险的研究。罕见致病 基因变异也会增加前列腺癌的总体和侵袭性风险，15%的转移病例携带 这样的变化。然而，由于测序成本较高，我们对罕见基因变异的贡献 前列腺癌的风险在很大程度上是基于候选基因研究，只有少数全外显子组或全基因组 迄今为止进行的研究具有足够大的样本量来发现新的稀有 变种/基因。此外，大多数男性包括在常见的和罕见的基因变异研究中 前列腺癌风险一直来自欧洲血统人群，限制了我们对前列腺癌遗传风险的了解 其他人群中的前列腺癌。这项研究的目的是阐明遗传因素对 不同人群患前列腺癌的总体和侵袭性风险，以及这些因素是如何 结合生活方式、环境和社会经济因素，更准确地描述 前列腺癌。在目标1中，我们将调查罕见和常见的基因变异对前列腺癌的贡献。 不同人群的癌症风险，目标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 一种已知的常见遗传风险变异的PR，可以通过罕见的致病变异携带者状态、生活方式来改变 各种因素，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。这项调查的结果有望确定新的机制 针对预防措施的新机制，并提高我们对复杂相互作用的理解 前列腺癌的遗传风险和可改变的风险因素。此外，这项调查预计将有所改善 我们识别总体和侵袭性前列腺癌风险增加的男性的能力，这可能对 筛查和医疗保健对前列腺癌预防的影响。

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.