Fine mapping and characterization of the 8q24 prostate cancer risk locus

描述(由申请人提供)：这项建议的最终目标是了解在多个种族群体中导致散发性前列腺癌的遗传因素。无论是体细胞遗传数据，还是最近的遗传遗传数据，都突出了染色体8q24上一个490kb的非编码区，在多个种族群体的前列腺癌生物学中发挥着重要作用。至少有7个等位基因与前列腺癌风险相关。这一发现代表了第一个被证实的遗传因素，该因素导致了普通人群中相当大的风险。目的1旨在确定在5个种族/民族人群中，8q24上导致前列腺癌风险的实际因果等位基因。首先，将通过对一个由48个人组成的多种族小组进行重新测序，来确定在这个490千碱基的区域中共同遗传变异的全面特征。其次，该区域的所有新SNPs将在特征良好的HapMap样本中进行基因分型，以创建所有常见遗传变异的完整集合。第三，我们之前的研究没有充分捕捉到任何新发现的变异(根据它们在HapMap中的相关性进行评估)，将测试MEC人群中前列腺癌的相关性(2788例前列腺癌病例和2613例对照)。目的2研究8q24基因遗传变异与体细胞基因表达和扩增表型的交集。为了这两个项目，总共将分析200个新鲜的冷冻前列腺癌组织(150名欧洲裔美国人和50名非洲裔美国人)。所有这些样本都将对已知的遗传风险等位基因以及在该项目过程中发现的任何等位基因进行基因分型。由于风险等位基因是非编码的，一种假设是，它们通过调节附近基因的表达水平来增加风险。表达研究将分两个阶段进行。首先，将通过平铺阵列来评估覆盖8q24区域3.8兆碱基的全面表达分析，以捕获注释和未注释的转录序列。代表风险等位基因分布极端的40名男性将被选为这一阶段的对象。其次，任何候选的差异表达序列都将在160名男性的独立样本中得到验证。确定了生殖系风险变异后，为探索生殖系和体细胞基因组之间的联系提供了独特的机会。8q区扩增是前列腺癌最常见的躯体病变之一。肿瘤通常被描述为经历了一个选择肿瘤相关性状的进化过程。基于这一框架的一种新方法将被应用于评估风险等位基因是否比预期更频繁地位于放大的8q染色体上。这一观察将提供令人信服的证据，证明风险等位基因是为肿瘤进化选择的，因此对肿瘤进化至关重要。与公共卫生的相关性：识别前列腺癌的潜在遗传因素提供了机会，以确定有可能罹患疾病的个体，并洞察可以调节以获得治疗益处的途径。我们的建议旨在找出DNA序列及其影响的基因的因果变化，以更好地了解该染色体区域是如何导致普通人群中相当一部分前列腺癌的。

DESCRIPTION (provided by applicant): The ultimate objective of this proposal is to understand the genetic elements driving sporadic prostate cancer across multiple ethnic groups. Both somatic and, more recently, inherited genetic data highlight a 490 kilobase (kb) noncoding region on chromosome 8q24 as playing a major role in prostate cancer biology across multiple ethnic populations. At least 7 alleles are associated with prostate cancer risk. This finding represents the first validated genetic factor responsible for an appreciable amount of risk in the general population. Aim 1 intends to identify the actual causal alleles at 8q24 contributing to prostate cancer risk across five racial/ethnic populations. First, full characterization of common genetic variation in this 490 kilobase region will be determined by resequencing a multiethnic panel of 48 individuals. Second, all novel SNPs in this region will be genotyped in the well characterized HapMap samples to create a complete collection of all common genetic variation. Third, any newly discovered variants not adequately captured by our previous studies (as assessed by their correlations in HapMap) will be tested for association with prostate cancer in the MEC populations (2,788 incident prostate cancer cases and 2,613 controls). Aim 2 focuses on the intersection between inherited variation at 8q24 and the somatic phenotypes of gene expression and amplification. A total of 200 fresh frozen prostate tumor tissues will be analyzed (150 European American men and 50 African American men) for both projects. All of these samples will be genotyped for the known inherited risk alleles as well as any that are discovered during the course of this project. Since the risk alleles are noncoding, one hypothesis is that they are elevating risk by modulating expression levels of a gene in the vicinity. The expression study will take place in two stages. First, a comprehensive expression analysis covering 3.8 megabases of the 8q24 region will be assessed by tiling arrays to capture both annotated and unannotated transcribed sequences. Forty men representing the extremes of the risk allele distribution will be selected for this stage. Second, any candidate differentially expressed sequence will be validated in an independent sample of 160 men. Having identified a germline risk variant provides the unique opportunity to explore connections between the germline and somatic genomes. Amplification of the 8q region is one of the most frequent somatic lesions in prostate cancer. Tumors are often described as undergoing an evolutionary process of selection for tumor related traits. A new method based on this framework will be applied to evaluate if the risk allele resides on an amplified 8q chromosome more often than expected by chance. This observation would provide compelling evidence that the risk allele is selected for and, therefore, critical for tumor evolution. RELEVANCE TO PUBLIC HEALTH: Identifying the genetic factors underlying prostate cancer provides the opportunity to identify individuals at risk of developing disease as well as to lend insight into pathways that can be modulated for therapeutic benefit. Our proposal aims to pinpoint the causal changes in DNA sequence and the gene that it influences to better understand how this chromosomal region is responsible for an appreciable fraction of prostate cancer in the general population.