A Genome-wide Association Study of Prostate Cancer in African Americans

描述(申请人提供)：前列腺癌是男性发病率和死亡率的主要原因之一。我们不了解前列腺癌的潜在病因，也不了解为什么非裔美国人等不同群体的前列腺癌发病率较高。前列腺癌的风险因素仍然难以捉摸，除了年龄，有前列腺癌家族史和非洲血统，直到最近利用基因组广泛关联研究(GWAS)发现了多个疾病风险基因。第一个这样的基因座是在8q24的一个“沙漠”基因中发现的，现在总共有至少30个基因座。从8q24开始发现的许多等位基因座落在内含子或附近的已知基因区。考虑到目前用于GWAS的工具的SNP密度，几乎所有已确定的风险基因都被发现是常见的等位基因变异，每个风险基因座患前列腺癌的相对风险往往不大，例如1.1-1.3。虽然这些个体风险等位基因频率的差异，特别是在8q24区域，可以部分解释非洲血统人群中更高的风险，但迄今为止检测到的所有风险基因座在前列腺癌家族风险中所占比例不超过20%-25%。有人假设，在已知功能候选基因区内或附近的基因座上，可能可以识别出不太常见或罕见的功能风险等位基因，这些不太常见或罕见的等位基因可能解释了LD中更常见的等位基因所识别的“信号”，以及更大的家族性和/或人群归因性风险。在这项应用中，我们组建了一个多机构的研究团队，这些研究人员在少数族裔人群中具有前列腺癌研究经验，他们愿意集中资源进行大规模尝试，以识别这种不太常见或罕见的等位基因。我们建议与哈佛大学的David Reich合作，他有能力对发现常见等位基因变异的风险区域进行条形码和大量DNA样本的深度测序。为了优化我们识别这些不太常见和罕见的变异的能力，我们建议包括来自多种族队列(日本人、非裔美国人、欧洲裔美国人、拉丁裔和夏威夷原住民)的4500例前列腺癌病例和对照，以及500例有前列腺癌家族史的非裔美国人前列腺癌病例，这些病例来自目前参与南加州大学非裔美国人合作GWA的人群。我们期望这一努力将大大促进各种不同种族/民族群体，包括非洲裔最高风险人群，对散发性和家族性前列腺癌遗传风险因素的了解。对已发现的风险基因座中功能性遗传变异的具体识别应指导未来预防、早期发现、预后甚至治疗措施的发展。 公共卫生相关性：该项目的目标是在全基因组关联研究中发现的大约30个等位基因中识别前列腺癌的不太常见和罕见的风险等位基因。为了这一努力，我们将利用多种族队列研究人群(非洲裔美国人、日本人、拉丁裔、欧洲裔美国人和夏威夷原住民)以及非洲裔美国人的几个关键群体的资源，这些人群是受资助的非洲裔美国人前列腺癌全基因组研究的一部分。更具体地说，我们建议对来自多种族队列研究的4500名前列腺癌患者和4500名对照患者以及另外500名有前列腺癌家族史的非裔美国人前列腺癌病例进行排序。

DESCRIPTION (provided by applicant): Prostate cancer is one of the leading causes of morbidity and mortality among men. We do not have an understanding of the underlying etiology of prostate cancer, or why different groups such as African Americans have higher rates of this disease. Risk factors for prostate cancer have remained elusive, other than age, having a family history of the disease and African ancestry, until recently with the discovery of multiple disease risk loci utilizing Genome Wide Association Studies( GWAS ). The first such loci were discovered in a gene " desert " in 8q24, and now the total number of loci number at least 30. Many of the allelic loci identified since those in 8q24, lie within introns or nearby known gene regions. Given the SNP density of the current tools used for GWAS, virtually all the risk loci identified have been found to be common allelic variants and the relative risk of prostate cancer from each such risk locus tends to be modest, e.g. 1.1-1.3. While differences in the frequency of such individual risk alleles, particularly in the 8q24 region, can partially account for the higher risk in populations of African ancestry, all the risk loci detected to date account for no more than 20-25% of the familial risk of prostate cancer. It has been hypothesized that less common or rare functional risk alleles might be identifiable in those loci located within or near to known functional candidate gene regions, and that such less common or rare alleles might explain both the " signal " identified by a more common allele in LD and a somewhat greater familial and/ or population attributable risk. In this application we have assembled a multi- institutional team of investigators with experience in prostate cancer research in minority populations who are willing to pool resources for a large scale attempt to identify such less common or rare alleles. We propose to collaborate with David Reich at Harvard who has the capability to bar code and pool large numbers of DNA samples for deep sequencing across the risk regions where the common allelic variants have been discovered. To optimize our ability to identify these less common and rare variants we propose to include 4500 prostate cases and controls from the Multiethnic Cohort ( Japanese, African American, European American, Latino and Native Hawaiian ) as well as 500 African American prostate cancer cases with a family history of prostate cancer from among those populations currently participating in the collaborative GWAS of African Americans being conducted at USC. We expect this effort to significantly advance knowledge of the genetic risk factors for sporadic and familial prostate cancer among a variety of different racial/ethnic groups, including the highest risk population of African ancestry. The specific identification of the functional genetic variants in the risk loci that have been discovered by GWAS should guide the development of future preventive, early detection, prognostic and even therapeutic measures. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify less common and rare risk alleles for prostate cancer in the approximately 30 allelic loci that have been discovered by genome wide association studies. For this effort, we will utilize the resources of the Multiethnic Cohort Study populations (African American, Japanese, Latino, European American, and Native Hawaiian) as well as several of the key populations of African Americans who are part of the funded African American prostate cancer genome wide association study. More specifically we propose to sequence 4500 individuals with prostate cancer and 4500 controls from the Multiethnic Cohort Study and an additional 500 African American prostate cancer cases with a family history of prostate cancer.