The Genetic Basis of Aggressive Prostate Cancer: The Role of Rare Variation

 描述（由申请人提供）：前列腺癌（PCa）是男性中最常见的癌症，今年在美国估计有220，000例新发病例和27，000例死亡。这些死亡中的绝大多数发生在约10-15%的诊断为侵袭性PCa的病例中。除了年龄，非洲血统和PCa家族史之外，PCa的已知风险因素很少，并且没有风险因素可以确定哪些男性会发展为侵袭性疾病或非侵袭性疾病。多条证据表明，侵略性PCa的实质性遗传成分。在过去的十年中，全基因组关联研究（GWAS）已经确定了超过100个常见的易感基因座，这些基因座共同占PCa家族风险的33%。这些基因座对侵袭性和非侵袭性疾病的风险贡献相等，这表明它们在PCa肿瘤演变的非常早期阶段发挥作用。最近的测序研究显示，BRCA 1/2和其他DNA修复途径基因等基因中存在罕见的编码变异（远低于1%），这些基因相对于非侵袭性疾病而言，侵袭性PCa的风险更大（3-5倍）。这些观察结果表明，侵袭性疾病的等位基因结构可能与整体PCa完全不同，并强调需要更大的努力集中在罕见的遗传变异（<1%）。这种变异谱代表了人类基因组中所有遗传变异的约80%，并且没有通过GWAS进行充分调查。在这项研究中，我们将采用多阶段的方法来揭示与侵袭性PCa相关的罕见变异基因。将对2,000例侵袭性病例和2,000例非侵袭性欧洲血统病例进行全外显子组测序（Aim 1a），然后进行单个位点的罕见变异分析和基因负荷检测，以确定侵袭性疾病的新易感基因座/基因。我们将在另外7,500例侵袭性和7,500例非侵袭性病例中通过靶向测序验证最显著相关的基因（约500个）（目标1b）。接下来，我们将研究在STHM 3试验中2,300例接受基于PSA和遗传风险评分分层活检的病例中鉴定的基因/变体的临床预测效用（目的2）。最后，我们将研究 Aim 1中鉴定的基因导致4，000名非洲血统男性中侵袭性PCa的风险更大（Aim 3）。通过这种分层的方法，我们期望显着推进知识的侵略性前列腺癌病因和健康的差距，以及指导发展的早期检测和预后策略的子集的男性谁是最容易受到这种致命的疾病形式。

 DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most common cancer in men with 220,000 new cases and 27,000 deaths estimated this year in the U.S. The vast majority of these deaths occur among the approximately 10-15% of cases diagnosed with aggressive PCa. There are few known risk factors for PCa beyond age, African descent and a family history of PCa, and there are no risk factors that can determine which men will develop aggressive versus non-aggressive disease. Multiple lines of evidence indicate a substantial heritable component of aggressive PCa. Over the past decade, genome-wide association studies (GWAS) have identified over 100 common susceptibility loci that collectively account for 33% of the familial risk of PCa. These loci contribute equally to risk of aggressive and non-aggressive disease which suggests they play a role in the very early stages of PCa tumor evolution. Recent sequencing studies have revealed rare coding variants (well under 1%) in genes such as BRCA1/2 and other DNA repair pathway genes that convey larger risks (3-5 fold) of aggressive PCa relative to non-aggressive disease. These observations suggest that the allelic architecture of aggressive disease may be quite different than overall PCa, and highlight the need for larger efforts focused on rare genetic variation (<1%). This spectrum of variation represents ~80% of all genetic variation in the human genome and is not adequately surveyed through GWAS. In this study, we will apply a multi-staged approach to reveal genes harboring rare variants that are associated with aggressive PCa. Whole-exome sequencing (Aim 1a) of 2,000 aggressive cases and 2,000 non-aggressive cases of European ancestry will be conducted followed by rare variant analysis of single sites and gene burden testing to identify novel susceptibility loci/genes for aggressive disease. We will validate the most significantly associated genes (~500) through targeted sequencing in an additional 7,500 aggressive and 7,500 non-aggressive cases (Aim 1b). Next, we will investigate the clinical predictive utility of the genes/variants identified in 2,300 cases in the STHM3 trial who are undergoing biopsy based on PSA and genetic risk score stratification (Aim 2). Last, we will examine whether the genes identified in Aim 1 contribute to the greater risk of aggressive PCa in 4,000 men of African ancestry (Aim 3). Through this tiered approach we expect to significantly advance knowledge of aggressive PCa etiology and health disparities as well as guide the development of early detection and prognostic strategies for the subset of men who are most susceptible to this fatal form of disease.