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 前列腺癌（PCa）的发病率和死亡率在非洲裔美国人（AA）男性中最高， 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（来自项目3），并评估生殖系 遗传学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。 我们希望这些综合生殖系-风险因素-体细胞分析能够揭示肿瘤亚组和共享的 在未来疾病进展和生存预测中具有临床重要性的生物学机制。 我们希望本项目的发现能显著提高对侵袭性前列腺癌易感性的认识。 以及PCa风险的种族/民族差异，并指导未来预防、早期发现和 AA男性的预后指标。