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

 描述(申请人提供)：前列腺癌(PCA)是男性中最常见的癌症，据估计，今年美国有22万新病例和2.7万人死亡。这些死亡中的绝大多数发生在大约10%-15%的侵袭性前列腺癌患者中。除了年龄、非洲血统和前列腺癌家族史之外，很少有已知的前列腺癌风险因素，也没有风险因素可以确定哪些男性会患上侵袭性疾病或非侵袭性疾病。多条证据表明侵袭性前列腺癌有相当多的可遗传成分。在过去的十年中，全基因组关联研究已经确定了100多个常见的易感基因座，这些易感基因总共占到了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同，这表明它们在PCa肿瘤进化的非常早期阶段发挥了作用。最近的测序研究发现，BRCA1/2和其他DNA修复途径基因中罕见的编码变异(远低于1%)传递了侵袭性前列腺癌比非侵袭性疾病更大的风险(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总体PCA截然不同，并强调需要更大的努力专注于罕见的遗传变异(&lt；1%)。这种变异谱占人类基因组中所有遗传变异的约80%，并没有通过GWAS进行充分的调查。在这项研究中，我们将应用多阶段方法来揭示含有与侵袭性前列腺癌相关的罕见变异的基因。将对2,000例侵袭性病例和2,000例非侵袭性欧洲血统的病例进行全外显子组测序(AIM 1a)，然后对单个位点进行罕见的变异分析和基因负担测试，以确定侵袭性疾病的新易感基因。我们将通过定向测序在另外7,500例侵袭性和7,500例非侵袭性病例中验证最显著的相关基因(~500)(目标1b)。接下来，我们将调查STHM3试验中2300例患者中识别的基因/变异的临床预测效用，这些患者正在接受基于PSA和遗传风险评分分层的活检(目标2)。最后，我们将研究是否 目标1中确定的基因导致4,000名非洲血统男性患侵袭性前列腺癌的风险更大(目标3)。通过这种分层次的方法，我们希望大大提高对侵袭性PCA病因和健康差异的了解，并指导为最容易感染这种致命疾病的男性子集制定早期检测和预后策略。

 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.