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

描述（由申请人提供）：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，或者为什么不同的群体，如非洲裔美国人有较高的发病率。前列腺癌的风险因素仍然难以捉摸，除了年龄，具有疾病家族史和非洲血统，直到最近利用全基因组关联研究（GWAS）发现多个疾病风险位点。第一个这样的基因座是在8 q24的基因“沙漠“中发现的，现在基因座的总数至少有30个。自8 q24以来鉴定的许多等位基因位点位于内含子内或已知基因区域附近。考虑到目前用于GWAS的工具的SNP密度，几乎所有鉴定的风险基因座都被发现是常见的等位基因变体，并且来自每个这样的风险基因座的前列腺癌的相对风险倾向于是适度的，例如1.1-1.3。虽然这些个体风险等位基因的频率差异，特别是在8 q24区域，可以部分解释非洲血统人群的较高风险，但迄今为止检测到的所有风险基因座占前列腺癌家族风险的不超过20-25%。据推测，不太常见或罕见的功能性风险等位基因可能在位于已知功能性候选基因区域内或附近的那些基因座中是可识别的，并且这种不太常见或罕见的等位基因可能解释LD中由更常见的等位基因识别的“信号“和更大的家族和/或群体归因风险。在本申请中，我们已经组建了一个多机构的研究人员团队，该团队具有在少数群体中进行前列腺癌研究的经验，他们愿意汇集资源进行大规模尝试以鉴定这种不太常见或罕见的等位基因。我们建议与哈佛的大卫赖希合作，他有能力对大量DNA样本进行条形码编码和合并，以便在发现常见等位基因变异的风险区域进行深度测序。为了优化我们识别这些不常见和罕见变异的能力，我们建议纳入4500例前列腺病例和来自多种族队列的对照。（日本人、非洲裔美国人、欧洲裔美国人、拉丁裔和夏威夷原住民）以及目前参与非裔美国人协作GWAS的人群中有前列腺癌家族史的500例非裔美国人前列腺癌病例，在USC进行。我们希望这项工作能够显著提高对各种不同种族/族裔群体中散发性和家族性前列腺癌遗传风险因素的认识，包括非洲血统的最高风险人群。GWAS发现的风险基因座中功能性遗传变异的特异性鉴定应指导未来预防、早期检测、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发现的大约30个等位基因位点中鉴定出不太常见和罕见的前列腺癌风险等位基因。为了这项工作，我们将利用多种族队列研究人群（非裔美国人，日本人，拉丁美洲人，欧洲裔美国人和夏威夷原住民）的资源，以及非裔美国人的几个关键人群，他们是资助的非裔美国人前列腺癌全基因组关联研究的一部分。更具体地说，我们建议从多种族队列研究中对4500名前列腺癌患者和4500名对照者以及另外500名有前列腺癌家族史的非洲裔美国人前列腺癌病例进行测序。

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.