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

利用来自不同生物库和队列的全外显子组序列数据来研究前列腺癌中罕见的编码变异

• 批准号: 10734712
• 负责人: Christopher Alan Haiman
• 金额: $ 76.59万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734712
• 关键词: African; African ancestry; Alleles; Allelic Imbalance; Asian; Asian ancestry; BRCA2 gene; Biological; Biology; CHEK2 gene; Cancer Patient; Candidate Disease Gene; Clinical; Code; DNA Repair Pathway; Data; Development; Diagnosis; Disease; Disease susceptibility; European; European ancestry; Family history of; Frequencies; Gene Expression Profile; Gene Frequency; Genes; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome; Germ-Line Mutation; Gleason Grade for Prostate Cancer; Heritability; Heterogeneity; Hispanic; Latino; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Minor; Modeling; Modification; Mutate; Mutation; PALB2 gene; Pathogenicity; Pathway interactions; Phenotype; Population; Protein Truncation; Proteins; Reporting; Resources; Risk; Sample Size; Somatic Mutation; Surveys; Susceptibility Gene; Testing; Time; Trans-Omics for Precision Medicine; Variant; biobank; clinical translation; cohort; cost; density; disease phenotype; disorder risk; diverse data; driver mutation; exome; genome wide association study; genome-wide; high risk; man; men; novel; personalized risk prediction; polygenic risk score; prevent; prospective; prostate cancer prevention; prostate cancer risk; rare variant; risk variant; screening; transcriptomics; tumor; whole genome

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.

抽象的 有充分的证据表明前列腺癌（PCA）是一种可遗传的表型。除了观察到更大的风险 在具有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 独立风险变体，解释了约40％的家族风险。人们越来越认识到很多 PCA的未知遗传力也可能是由于低次要等位基因频率的变异（<1％）引起的。虽然很大，多 祖先基因组全基因组参考板（例如，最高）已被开发出来，以促进研究较少的研究 普通等位基因（降至0.1％），它们不能用来列举和准确研究非常罕见的等位基因 只能通过测序表征。 DNA修复途径基因中的致病变异（例如，BRCA2， 通过候选基因研究确定的ATM，NBN，CHEK2，PALB2）为极端的支持提供了强有力的支持 罕见（<0.1％）蛋白质编码变化，导致整体PCA和侵略性疾病敏感性。 不幸的是，我们在全面调查和研究非常罕见的差异基因组的能力方面仍然有限 或由于较高的测序成本而全外观，限制了当前的样本量。在这里，我们建议将现有 从多功能生物库和队列到全基因组和全基因组（WES）和全基因组（WGS）序列数据 对PCA的稀有编码变化进行了首次大规模研究，并整合肿瘤体细菌和种系 突变数据以阐明基因风险关联的生物学。在AIM 1中，我们将利用现有的WES数据 > 90,000个PCA案件（58,000个欧洲血统，20,000名非洲血统，4,000个亚洲血统和6,700 拉丁裔/西班牙裔）和> 500,000个在美国和英国的生物库中的控件 总体PCA和侵略性疾病表型的分析。在AIM 2中，我们将研究 罕见的编码变体和多基因风险评分（PRS）在整体PCA和侵略性疾病的风险和估计中 前瞻性生物库中稀有编码变体和PR的综合效果的绝对风险 跨种群。在AIM 3中，我们将整合体细胞肿瘤和种系变异数据，以告知基因和 PCA和攻击性疾病涉及的生物途径。为此，我们组装了一个躯体 来自WES和 WGS研究，包括2,000个具有转录组数据的研究。我们希望这项研究能够提供最全面的 迄今为止，PCA的PCA罕见编码变化以及迄今为止的PCA罕见编码变化。从中的发现 研究将通过告知个性化风险预测和发展，将立即进行临床翻译 基于风险的新型筛查策略，用于整体和积极的PCA。整合种系和躯体数据将 还定义了可能在临床上了解如何治疗和预防的生物学机制 人群中的PCA和致命疾病。