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

项目 2：非洲血统男性对侵袭性前列腺癌的遗传易感性特征

• 批准号: 10447154
• 负责人: Christopher Alan Haiman
• 金额: $ 14.43万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447154
• 关键词: 8q24; Address; Admixture; Africa; African; African American; African ancestry; Alleles; Architecture; Biological; Body mass index; Caribbean region; Categories; Characteristics; Clinical; Code; Data; Development; Disease; Disease Progression; Early Diagnosis; Environmental Risk Factor; Ethnic group; Europe; Event; Frequencies; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic Variation; Genome; Genome Scan; Goals; Immune; Immunity; Incidence; Inflammation; Investigation; Knowledge; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Meta-Analysis; Modeling; Molecular Genetics; Mutate; Pathway interactions; Population; Predisposition; Prevalence; Prevention strategy; Preventive; Proteins; Recurrence; Relative Risks; Research; Resources; Risk; Risk Factors; Role; Sampling; Smoking; Stress; Subgroup; Susceptibility Gene; Testing; Variant; cancer genetics; case control; cohort; disorder risk; ethnic difference; exome; exome sequencing; genetic variant; genome wide association study; genome-wide; high risk; lifestyle factors; long-standing disparities; man; men; mortality; novel; prognostic; programs; prostate cancer risk; racial and ethnic; racial and ethnic disparities; rare variant; risk variant; screening; secondary analysis; social; tumor; tumor microenvironment

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.

摘要 – 项目 2 与任何其他国家相比，非洲裔美国 (AA) 男性的前列腺癌 (PCa) 发病率和死亡率最高 其他种族/族裔人口。这些长期存在的种族/民族差异尚未得到解释。基因组- 在 AA 男性中进行的 PCa 广泛关联研究为 AA 男性中的遗传差异提供了明确的支持。 PCa 跨人群的等位基因结构以及对潜在人群遗传基础的有力支持 风险的差异。还有多种证据支持遗传因素对攻击性/致命性的影响 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 PCa 易感性。癌症的发生和进展涉及种系 然而，迄今为止，种系风险位点和体细胞基因组的发现和表征工作 PCa 的改变是单独进行的。我们建议，有必要采取大规模努力 发现了导致 AA 男性侵袭性前列腺癌易感性的常见和罕见遗传变异。在 此外，通过结合种系和体细胞变异，我们期望揭示新的生物学机制 潜在的 PCa 攻击性。在这个项目中，我们试图找出与 PCa 相关的遗传因素 非洲血统男性的攻击性。更具体地说，在目标 1 中，我们计划寻找共同的种系 在包含 5,700 例高危病例（T3/T4 期或 格里森 8+ 或 PSA>20 ng/ml），5,600 例中危病例（T2b/T2c 期或格里森 7 或 PSA 10-20 ng/ml）和 3,800 例低危 PCa 病例（T1/T2a 期和 Gleason ≤ 6 且 PSA<10 ng/ml）来自 RESPOND 队列和非洲祖先 PCa 联盟 (AAPC)。在目标 2 中，我们将进行外显子组 对 AAPC 的 15,000 个 PCa 病例以及 5,000 个对照进行测序，以研究 PCa 侵袭性的罕见变化。在目标 1 和 2 中，单变异和基因负荷关联测试 将通过高风险疾病与低风险​​疾病的个案比较以及多项名义进行比较 按风险类别进行多级逻辑回归。在目标 3 中，我们将测试种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（来自项目 3）并评估是否有种系 遗传和生活方式因素与体细胞特征和转录状态相互作用，以区分 PCa 风险特征。 我们期望这些综合的种系风险因素体细胞分析能够揭示肿瘤亚组和共享的 对未来疾病进展和生存预测具有临床重要意义的生物学机制。 我们预计该项目的研究结果将显着增进对侵袭性 PCa 易感性的了解 以及 PCa 风险的种族/民族差异，并指导未来预防、早期检测和治疗的发展 AA 男性的预后测量。