Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Immunity and Stress (RESPOND)

摘要-RESPOND的项目2（来自家长资助） 与任何男性相比，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。这些长期存在的种族/民族差异尚未得到解释。基因组- 在AA男性中进行的PCa的广泛关联研究为以下遗传差异提供了明确的支持： PCa在人群中的等位基因结构和对人群遗传基础的有力支持 风险的差异。也有多条证据支持遗传因素对侵袭性/致命性 PCa，包括最近的测序研究，这些研究为罕见（<1%）的蛋白质编码变异提供了支持， 导致侵袭性前列腺癌易感性。癌症的发展和进展涉及生殖细胞和生殖细胞。 然而，迄今为止，发现和表征生殖系风险基因座和体细胞基因组的努力， PCa的改变是单独进行的。我们建议，必须作出大规模努力， 发现常见和罕见的遗传变异，有助于积极的前列腺癌的易感性AA男性。在 此外，通过结合生殖细胞和体细胞变异，我们希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PCa相关的遗传因素， 非洲血统的男人的侵略性。更具体地说，在目标1中，我们计划寻找共同的种系 在5，700例高风险（T3/T4期或T4期）病例的病例-病例GWAS中，与PCa风险特征相关的变异 Gleason 8+或PSA>20 ng/ml），5，600例中危（T2 b/T2 c或Gleason 7或PSA 10-20 ng/ml）和3，800例低风险PCa（T1/T2 a期和Gleason ≤ 6和PSA<10 ng/ml）患者。 RESPOND队列和非洲制药PCa联盟（AAPC）。在目标2中，我们将进行外显子组 对来自AAPC的这15，000例PCa病例以及5，000例对照进行测序，以研究 PCa攻击性的罕见变异。在目标1和2中，单变异和基因负荷关联检验 将通过高风险疾病与低风险疾病的病例-病例比较以及多名 按风险类别进行多分类logistic回归。在目标3中，我们将测试生殖系遗传学之间的关系， AA男性的生活方式因素和体细胞肿瘤特征，并评估生殖系遗传学和生活方式 因子与体细胞谱和转录状态相互作用以区分PCa风险谱。我们预计这些 综合生殖系-风险因素-体细胞分析，揭示肿瘤亚群和共同的生物学机制 在未来预测疾病进展和生存方面具有重要临床意义。我们希望调查结果 从本项目中，显著提高了对侵袭性PCa和种族/民族易感性的认识 PCa风险的差异，并指导未来预防，早期发现和预后的发展 AA制的男人。

Abstract – Project 2 of RESPOND (from Parent Grant) 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 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.