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个种族群体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8 q24上490 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，该因素在一般人群中引起了可观的风险。目的1旨在确定在5个种族/民族人群中8 q24的实际致病等位基因对前列腺癌风险的贡献。首先，将通过对48个个体的多种族小组进行重新测序来确定该490个酶区域中常见遗传变异的完整特征。第二，将在充分表征的HapMap样品中对该区域中的所有新SNP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获的任何新发现的变异（根据HapMap中的相关性进行评估）将在MEC人群（2，788例前列腺癌病例和2，613例对照）中检测与前列腺癌的相关性。目的2关注8 q24的遗传变异与基因表达和扩增的体细胞表型之间的交叉。两个项目共分析200例新鲜冷冻前列腺肿瘤组织（150例欧洲裔美国男性和50例非洲裔美国男性）。所有这些样本都将进行已知遗传风险等位基因以及本项目过程中发现的任何等位基因的基因分型。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。表达研究将分两个阶段进行。首先，将通过平铺阵列评估覆盖8 q24区域的3.8兆碱基的综合表达分析，以捕获注释和未注释的转录序列。将选择40名代表风险等位基因分布极端的男性用于该阶段。第二，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。确定生殖系风险变异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。8 q区域的扩增是前列腺癌中最常见的体细胞病变之一。肿瘤通常被描述为经历一个选择肿瘤相关性状的进化过程。基于此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偶然驻留在扩增的8 q染色体上。这一观察结果将提供令人信服的证据，表明风险等位基因是选择的，因此对肿瘤演变至关重要。与公共卫生的关系：确定前列腺癌的遗传因素提供了机会，以确定个人的发展疾病的风险，以及提供洞察的途径，可以调节治疗效益。我们的提案旨在查明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负责一般人群中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.