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)是一种可遗传的表型。除了观察到的更大风险之外 在有前列腺癌家族史的男性中，全基因组关联研究(GWAS)已经确定了400多个共同的 独立风险变量，可解释约40%的家族风险。越来越多的人认识到，许多 PCA的未知遗传率也可能是由于低等位基因频率(1%)的变异所致。虽然规模很大，但多个 已经开发了祖先全基因组参考板(例如，TOPMed)以促进对LESS的研究 常见等位基因(低至0.1%)，它们不能用来列举和准确研究非常稀有的等位基因 只能通过测序来表征。DNA修复途径基因的致病变异(例如，BRCA2， ATM、NBN、CHEK2、PALB2)，通过候选基因研究鉴定，为 罕见的(0.1%)蛋白质编码变异导致总体前列腺癌和侵袭性疾病易感性。 不幸的是，我们全面调查和研究非常罕见的变异基因组的能力仍然有限- 或外显子组，因为测序成本高，限制了当前的样本大小。在这里，我们建议将现有的 来自多个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 首次大规模研究前列腺癌罕见编码变异并整合肿瘤体细胞和种系 突变数据，以阐明基因-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例前列腺癌(58,000例欧洲血统，20,000例非洲血统，4,000例亚洲血统和6,700例亚洲血统 拉丁裔/西班牙裔)和500,000人在美国和英国的生物库和队列中进行控制，并在整个外基因组范围内进行 总体PCA和侵袭性疾病表型的分析。在目标2中，我们将检查以下各项的综合效果 罕见的编码变异和多基因风险评分(PRS)对总体PCa和侵袭性疾病的风险和估计 在预期的生物库和队列中，罕见编码变体和PR的联合作用的绝对风险 在不同人群之间。在目标3中，我们将整合体细胞肿瘤和生殖系变异数据，以告知基因和 参与前列腺癌和侵袭性疾病的生物学途径。为了达到这个目的，我们组建了一个躯体 来自WES和WES的7,000名前列腺癌患者的种系外显子/PRS数据和体细胞突变图谱的来源 WGS研究，包括具有转录数据的2000人。我们预计这项研究将提供最全面的 到目前为止，对不同种群之间罕见的PCA编码变异进行了有力的检查。由此得出的结论 这项研究将立即转化为临床，告知个性化风险预测和 新的基于风险的筛选策略，适用于全面和积极的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 在人群中传播前列腺癌和致命疾病。

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.