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外 在有 PCa 家族史的男性中，全基因组关联研究 (GWAS) 已发现 400 多种常见的疾病 独立风险变异，可以解释约 40% 的家族风险。人们越来越认识到，许多 PCa 的未知遗传性也可能是由于次要等位基因频率低（<1%）的变异造成的。虽然规模大、多 祖先全基因组参考面板（例如 TOPMed）的开发是为了促进更少的研究 常见等位基因（低至 0.1%），因此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 修复途径基因的致病性变异（例如 BRCA2、 通过候选基因研究确定的ATM、NBN、CHEK2、PALB2）为超强的 罕见（<0.1%）的蛋白质编码变异导致整体前列腺癌和侵袭性疾病的易感性。 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- 由于高测序成本，限制了当前的样本量。在这里，我们建议结合现有的 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 对 PCa 中罕见的编码变异进行首次大规模研究，并将肿瘤体细胞和种系整合 突变数据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 名欧洲血统、20,000 名非洲血统、4,000 名亚洲血统和 6,700 名 拉丁裔/西班牙裔）以及美国和英国生物库和队列中超过 500,000 个对照，并进行全外显子组研究 总体 PCa 和侵袭性疾病表型的分析。在目标 2 中，我们将检查以下因素的综合影响： 罕见的编码变异和多基因风险评分 (PRS) 对 PCa 和侵袭性疾病的总体风险进行评估 前瞻性生物库和队列中罕见编码变异和 PRS 综合影响的绝对风险 跨人群。在目标 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 涉及 PCa 和侵袭性疾病的生物学途径。为了这个目标，我们组装了一个体细胞 超过 7,000 名 PCa 患者的资源，包括来自 WES 和 PRS 的种系外显子组/PRS 数据和体细胞突变分析 WGS 研究，包括超过 2,000 项转录组数据。我们希望这项研究能够提供最全面的 迄今为止，对跨人群 PCa 罕见编码变异进行了强有力的检查。由此得出的结论 研究将通过提供个性化风险预测和开发来立即进行临床转化 针对整体和侵袭性 PCa 的新颖的基于风险的筛查策略。整合种系和体细胞数据将 还定义了对于理解如何治疗和预防可能具有临床重要意义的生物学机制 PCa 和人群中的致命疾病。