Project 2: Characterizing Genetic Susceptibility to Aggressive Prostate Cancer in Men of African Ancestry

摘要-项目2 非裔美国人(AA)男性的前列腺癌(PCA)发病率和死亡率最高 其他种族/民族人口。这些长期存在的种族/民族差异尚未得到解释。基因组- 在再生障碍性贫血患者中进行的广泛关联研究为遗传性差异提供了明确的支持 群体间主成分分析的等位基因结构及其对群体遗传基础的有力支持 风险差异。也有多条证据支持基因对攻击性/致命性的贡献。 PCA包括最近的测序研究，这些研究为罕见的(1%)蛋白质编码变异提供了支持 导致进攻性前列腺癌易感性。癌症的发生和发展涉及生殖系 然而，到目前为止，种系风险基因座和体细胞基因组的发现和表征工作 PCA的改变是在孤立的情况下进行的。我们建议有必要进行大规模的努力，以实现 发现导致AA男性侵袭性前列腺癌易感性的常见和罕见的基因变异。在……里面 此外，通过结合生殖系和体细胞变异，我们有望揭示新的生物学机制 潜在的PCA攻击性。在这个项目中，我们试图确定与前列腺癌相关的遗传因素 非洲血统男人身上的攻击性。更具体地说，在目标1中，我们计划搜索共同的生殖系 5,700例高危患者(T3/T4期或 Gleason 8+或PSA；20 ng/ml)，5,600例中等风险(T2b/T2C或Gleason 7或PSA 10-20 和3,800例低危前列腺癌(T1/T2a期、格里森≤6和PSA；10 ng/ml)。 响应队列和非洲血统防止虐待儿童联盟(AAPC)。在目标2中，我们将进行exome 对这15,000例PCa病例以及来自AAPC的5,000名对照进行测序，以调查 PCA攻击性的罕见变异。在目标1和目标2中，单变异和基因负荷关联测试 将通过高危疾病与低风险疾病的病例-病例比较以及按多个名义进行 按风险类别进行多分类Logistic回归分析。在目标3中，我们将测试生殖系遗传学、 AA男性的生活方式因素和躯体肿瘤特征(来自项目3)，并评估生殖系 遗传和生活方式因素与体细胞分布和转录状态相互作用，以区分PCa风险分布。 我们希望这些综合的生殖系-风险因素-体细胞分析能够揭示肿瘤亚群和共享 对未来疾病进展和生存的预测具有重要临床意义的生物学机制。 我们期望这个项目的发现将大大提高对侵袭性前列腺癌易感性的认识 和人种/人种在前列腺癌风险方面的差异，并指导今后预防、早期发现和 AA患者的预后指标。

Abstract – Project 2 Prostate cancer (PCa) incidence and mortality rates are highest in African American (AA) men compared to any other racial/ethnic population. These long-standing racial/ethnic differences have yet to be explained. Genome- wide association studies of PCa conducted in AA men have provided clear support for genetic differences in the allelic architecture of PCa across populations and strong support for a genetic basis underlying population differences in risk. There are also multiple lines of evidence to support a genetic contribution to aggressive/fatal PCa including recent sequencing studies that have provided support for rare (<1%) protein coding variation in contributing to aggressive PCa susceptibility. Cancer development and progression involves both the germline and somatic genomes however to date, discovery and characterization efforts of germline risk loci and somatic alterations in PCa have been conducted in isolation. We propose that large-scale efforts are warranted for the discovery of common and rare genetic variation that contributes to aggressive PCa susceptibility in AA men. In addition, through combining germline and somatic variation we expect to reveal novel biological mechanisms underlying PCa aggressiveness. In this Project, we seek to identify genetic factors that are associated with PCa aggressiveness in men of African ancestry. More specifically, in Aim 1, we plan to search for common germline variants associated with PCa risk profiles in a case-case GWAS of 5,700 cases with high-risk (stage T3/T4 or Gleason 8+ or PSA>20 ng/ml), 5,600 cases with intermediate-risk (stage T2b/T2c or Gleason 7 or PSA 10-20 ng/ml) and 3,800 cases with low-risk PCa (stage T1/T2a and Gleason ≤ 6 and PSA<10 ng/ml) from the RESPOND cohort and the African Ancestry PCa Consortium (AAPC). In Aim 2, we will conduct exome sequencing of these 15,000 PCa cases as well as 5,000 controls from AAPC to investigate the contribution of rare variation on PCa aggressiveness. In both Aims 1 and 2, single variant and gene burden association testing will be conducted by case-case comparisons of high- vs. low-risk disease, as well as by multi-nominal polytomous logistic regression by risk category. In Aim 3, we will test the relationship between germline genetics, lifestyle factors and somatic tumor characteristics (from Project 3) in AA men and assess whether germline genetics and lifestyle factors interact with somatic profiles and transcription states to distinguish PCa risk profiles. We expect these integrated germline-risk factor-somatic analyses to reveal tumor subgroups and shared biological mechanisms that are clinically important in the future prediction of disease progression and survival. We expect the findings from this Project to significantly advance knowledge of susceptibility to aggressive PCa and racial/ethnic disparities in PCa risk, and to guide the development of future preventive, early detection and prognostic measures for AA men.