Leveraging whole-exome sequence data from diverse biobanks and cohorts to study rare coding variation in prostate cancer

摘要 有强有力的证据表明，前列腺癌（PCa）是一种遗传表型。除了观察到的更大风险外， 在有PCa家族史的男性中，全基因组关联研究（GWAS）已经确定了400多个常见的PCa基因。 独立的风险变量，解释了约40%的家族风险。人们日益认识到， PCa的未知遗传性也可能是由于低次要等位基因频率（<1%）的变体。虽然大，多- 祖先全基因组参考组（例如，TOPMed）的开发，以促进研究较少 常见的等位基因（低至0.1%），它们不能用于枚举和准确研究非常罕见的等位基因， 只能通过测序来表征。DNA修复途径基因中的致病性变体（例如，BRCA2， ATM，NBN，CHEK 2，PALB 2），通过候选基因研究确定，提供了强有力的支持， 罕见的（<0.1%）蛋白质编码变异导致总体PCa和侵袭性疾病易感性。 不幸的是，我们在全面调查和研究非常罕见的变异基因组方面的能力仍然有限- 或外显子组范围的，这是由于高测序成本，限制了当前的样品大小。在此，我们建议将现有的联合收割机 来自多祖先生物库和队列的全外显子组（WES）和全基因组（WGS）序列数据， 进行首次大规模研究PCa中罕见的编码变异，并整合肿瘤体细胞和生殖细胞 突变数据来阐明基因风险关联的生物学。在目标1中，我们将利用现有的WES数据， > 90，000例PCa病例（58，000例欧洲血统，20，000例非洲血统，4，000例亚洲血统和6，700例 拉丁裔/西班牙裔）和> 500，000名对照，并在美国和英国的生物库和队列中进行外显子组范围的 分析总体PCa和侵袭性疾病表型。在目标2中，我们将研究以下因素的综合影响： 罕见编码变异和多基因风险评分（PRS）对总体PCa和侵袭性疾病风险的评估 前瞻性生物库和队列中罕见编码变体和PRS联合效应的绝对风险 在人群中。在目标3中，我们将整合体细胞肿瘤和生殖系变异数据， 生物学途径参与PCa和侵袭性疾病。为此目的，我们组装了一个体细胞 > 7，000名PCa患者的资源，具有来自WES的生殖系外显子组/PRS数据和体细胞突变谱， WGS研究，包括> 2，000个转录组学数据。我们希望这项研究能够提供最全面的 以及迄今为止对人群中PCa罕见编码变异的有效性检查。时发现的问题 这项研究将通过提供个性化的风险预测和开发 新的基于风险的筛查策略，用于全面和积极的PCa。整合生殖系和体细胞数据将 还定义了可能对理解如何治疗和预防具有临床重要意义的生物学机制。 PCa与人群中的致命疾病。

Abstract There is strong evidence that prostate cancer (PCa) is a heritable phenotype. In addition to greater risk observed in men with a family history of PCa, genome-wide association studies (GWAS) have identified over 400 common independent risk variants, which explain ~40% of the familial risk. It is increasingly recognized that much of the unknown heritability for PCa may also be due to variants of low minor allele frequency (<1%). While large, multi- ancestry genome-wide reference panels (e.g., TOPMed) have been developed to facilitate studies of less common alleles (down to 0.1%), they cannot be used to enumerate and accurately study very rare alleles that can only be characterized via sequencing. Pathogenic variants in DNA repair pathway genes (e.g., BRCA2, ATM, NBN, CHEK2, PALB2), identified through candidate gene studies, provide strong support for exceedingly rare (<0.1%) protein coding variation contributing to overall PCa and aggressive disease susceptibility. Unfortunately, we remain limited in our ability to comprehensively survey and study very rare variation genome- or exome-wide due to high sequencing costs, limiting current sample sizes. Here, we propose to combine existing whole-exome (WES) and whole-genome (WGS) sequence data from multi-ancestry biobanks and cohorts to conduct the first, large-scale study of rare coding variation in PCa and to integrate tumor somatic and germline mutation data to elucidate the biology of gene-risk associations. In Aim 1, we will leverage existing WES data for >90,000 PCa cases (58,000 European ancestry, 20,000 African ancestry, 4,000 Asian ancestry and 6,700 Latino/Hispanic) and >500,000 controls within biobanks and cohorts in the US and UK and conduct exome-wide analyses of overall PCa and aggressive disease phenotypes. In Aim 2, we will examine the combined effect of rare coding variants and a polygenic risk score (PRS) on risk of overall PCa and aggressive disease and estimate absolute risks for the combined effects of rare coding variants and PRS in prospective biobanks and cohorts across populations. In Aim 3, we will integrate somatic tumor and germline variation data to inform genes and biological pathways involved in PCa and aggressive disease. For this Aim, we have assembled a somatic resource of >7,000 PCa patients with germline exome/PRS data and somatic mutation profiling from WES and WGS studies, including >2,000 with transcriptomic data. We expect this study to provide the most comprehensive and well-powered examination of rare coding variation in PCa across populations to date. Findings from this study will have immediate clinical translation by informing personalized risk prediction and the development of novel risk-based screening strategies for overall and aggressive PCa. Integrating germline and somatic data will also define biological mechanisms that may be clinically important for understanding how to treat and prevent PCa and lethal disease across populations.