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

描述（由申请人提供）：本提案的最终目标是了解在多种族人群中驱动散发性前列腺癌的遗传因素。体细胞和最近的遗传数据都强调了染色体8q24上490千碱基（kb）的非编码区在多个种族人群的前列腺癌生物学中起着重要作用。至少有7个等位基因与前列腺癌风险有关。这一发现首次证实了遗传因素在普通人群中造成相当数量的风险。目的1旨在确定在5个种族/民族人群中与前列腺癌风险相关的8q24的实际因果等位基因。首先，对这个490千碱基区域的共同遗传变异的全面表征将通过对48个个体的多种族小组进行重测序来确定。其次，该区域的所有新snp将在具有良好特征的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，我们将在MEC人群（2,788例前列腺癌病例和2,613例对照）中测试任何未被我们之前的研究充分捕获的新发现的变异（通过其在HapMap中的相关性进行评估）与前列腺癌的关联。目的2侧重于8q24遗传变异与基因表达和扩增的体细胞表型之间的交集。这两个项目将分析200个新鲜冷冻前列腺肿瘤组织（150名欧洲裔美国男性和50名非洲裔美国男性）。所有这些样本将对已知的遗传风险等位基因以及在本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提高风险。这项表达研究将分两个阶段进行。首先，通过平铺阵列对覆盖8q24区域3.8兆碱基的综合表达分析进行评估，以捕获带注释和未注释的转录序列。这一阶段将选出代表风险等位基因分布极端的40名男性。其次，任何候选差异表达序列将在160名男性的独立样本中进行验证。确定了种系风险变异为探索种系和体细胞基因组之间的联系提供了独特的机会。8q区扩增是前列腺癌中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。一种基于此框架的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驻留在扩增的8q染色体上。这一观察结果将提供令人信服的证据，证明风险等位基因是被选择的，因此对肿瘤进化至关重要。与公共卫生的相关性：确定前列腺癌的遗传因素为确定有患病风险的个体提供了机会，也为了解可调节的治疗益处途径提供了机会。我们的建议旨在查明DNA序列的因果变化及其影响的基因，以更好地了解该染色体区域如何在一般人群中负责相当一部分前列腺癌。

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.