The role of germline and somatic DNA changes at 8q24 in PCa risk

描述(申请人提供)：8q24序列变异和前列腺癌风险之间的遗传关联最初是在2006年报道的，并在几项确证研究中得到持续重复，包括我们利用约翰·霍普金斯医院的大型医院病例/对照人群进行的研究。虽然这种关联是迄今为止在前列腺癌中最令人信服的遗传学发现，但关于8q24的前列腺癌遗传关联的完整图景、8q体细胞获得在遗传关联中的作用以及特定基因是否与该关联有关仍然存在许多重要的问题。这项研究的总体假设是，位于8q24的生殖系和体细胞遗传变异与前列腺癌风险相关。具体地说，我们假设：1)8q24处的多个生殖系变异与欧洲美国人和非裔美国人的前列腺癌风险和侵袭性有关；2)8q24处的生殖系和体细胞遗传变化对前列腺癌风险和侵袭性有共同影响；以及3)8q24基因变异通过改变侧翼区域和基因组其他地方的基因表达来影响前列腺癌风险(顺式效应)和其他区域(反式效应)。为了验证这些假设，我们从维克森林大学人类基因组学中心和约翰霍普金斯医院(JHH)组建了一个研究小组，并将结合我们在遗传关联研究、体细胞DNA分析和RNA/蛋白质分析方面的优势。我们有一个独特的机会来检验我们关于生殖系和体细胞变化的假设，因为JHH中有大量欧洲裔美国人(N=400)和非裔美国人(N=400)的冷冻前列腺组织。我们有两个具体目标。首先，我们将在这800个肿瘤中测试相关的生殖系风险变异和8q24的体细胞遗传变化对PCa风险和疾病侵袭性的联合影响。其次，我们将通过评估生殖系和体细胞8q24变异与8q24侧翼区域和基因组其他地方基因的RNA/蛋白质表达之间的相关性，来确定8q24风险变异对前列腺组织基因表达的顺式或反式影响。我们的研究结果将提高我们对迄今为止最突出的基因发现的理解，并可能对疾病预测、诊断和治疗产生重要影响。公共卫生相关性：在这项研究中，我们将结合两种主要的研究方法，使我们能够同时检查肿瘤中的遗传基因变化和获得性基因变化。目标将是使用这些方法来了解8q24基因变异在前列腺癌风险中的作用。因为8q24基因变异与前列腺癌之间的关联是迄今为止最令人信服的关联发现，我们的研究有一个极好的机会来促进我们在前列腺癌的病因、诊断和治疗方面的知识。

DESCRIPTION (provided by applicant): A genetic association between 8q24 sequence variants and prostate cancer risk was initially reported in 2006 and has been consistently replicated in several confirmation studies, including our study utilizing a large hospital-based case/control population from Johns Hopkins Hospital. While the association is the most convincing genetic finding in prostate cancer to date, many important questions remain regarding the complete picture of PCa genetic association at 8q24, the role of 8q somatic gains in the context of the genetic association, and whether a specific gene is implicated by the association. The overall hypothesis of this study is that germline and somatic genetic variants at 8q24 are associated with PCa risk. Specifically, we hypothesize that 1) multiple germline variants at 8q24 are associated with PCa risk and aggressiveness in European Americans and in African Americans; 2) germline and somatic genetic changes at 8q24 have a joint effect on PCa risk and aggressiveness; and 3) 8q24 genetic variants affect PCa risk by altering gene expression in the flanking regions (cis-effect) and elsewhere in the genome (trans-effect). To test these hypotheses, we have assembled a research team from The Wake Forest University Center for Human Genomics and Johns Hopkins Hospital (JHH), and will combine our strengths in genetic association studies, somatic DNA analyses, and RNA/protein analyses. We have a unique opportunity to test our hypothesis regarding germline and somatic changes because of the large number of frozen prostate tissues in European Americans (N=400) and African Americans (N=400) available in the JHH. We have two specific aims. First, we will test the joint effect of implicated germline risk variants and somatic genetic changes at 8q24 on PCa risk and aggressiveness of the disease among these 800 tumors. Second, we will identify cis- or trans-effects of 8q24 risk variants on gene expression in prostate tissues by assessing correlation between the germline and somatic 8q24 variants and RNA/protein expression of genes in the 8q24 flanking region and elsewhere in the genome. Results from our study will improve our understanding of the most prominent genetic finding to date and may have important implications in disease prediction, diagnosis, and treatment. PUBLIC HEALTH RELEVANCE: In this study we will combine two major research methods, allowing us to simultaneously examine inherited genetic changes and acquired genetic changes in tumors. The goal will be to use these approaches to understand the role of 8q24 genetic variants in prostate cancer risk. Because the association between 8q24 genetic variants and prostate cancer is the most convincing association finding to date, our study has an excellent opportunity to advance our knowledge in the etiology, diagnosis, and treatment of prostate cancer.