Genetic Variation Affecting Epigenome and Breast Cancer Susceptibility

描述（由申请人提供）：全基因组关联分析最近发现了几个低渗透乳腺癌易感基因，然而，绝大多数乳腺癌遗传易感性尚待表征。考虑到乳腺癌肿瘤中的甲基化改变，可以认为异常或受损的表观基因组调控可能是乳腺癌易感性的潜在机制。在这项研究中，我们建议整合从最近的GWAS和一个独立的候选途径单倍型标记（ht）的方法，以确定DNA变异的表观遗传调控（ERG）基因，赋予乳腺癌的风险升高的可用数据。捕获102个候选表观遗传调控基因中的常见遗传变异的989个标记SNP（tSNP）的组将在病例/对照关联分析中分别测试单一效应以及作为低等位率乳腺癌易感性等位基因的上位性基因-基因相互作用。该项目将采用两步法来最大化统计功效;包括具有乳腺癌强家族史的病例队列（N=500）以及非乳腺癌病例（N=2000）和健康对照（N=2000）的大型队列。病例和对照将从两个人群中抽取，即德系犹太血统（AJ）的隔离人群（1300例病例，1000例对照）和主要为非AJ欧洲血统的样本人群（1200例病例，1000例对照）。最后，将在乳腺癌协会联盟（BCAC）内对约10，000例乳腺癌病例和约10，000例对照进行最显著相关性的复制。拟议的项目将提供迄今为止第一个基因组方法，利用表观遗传调控途径的系统分析，以确定对乳腺癌遗传易感性的复杂影响。这项研究的结果将扩展先前GWAS的观察结果，并可能反过来提供进一步的生物学证据，阐明异常表观基因组在乳腺癌肿瘤发生中的作用。 公共卫生相关性：后基因组时代生物技术的发展为寻找乳腺癌易感基因提供了新的策略。然而，尽管做出了巨大的努力，但超过70%的遗传性乳腺癌的遗传缺陷尚未被确定。人类的遗传信息在很大程度上受“非DNA”事件的调控，称为表观基因组。据描述，表观基因组调控在包括乳腺肿瘤在内的许多癌症中存在缺陷。我们认为，在一些乳腺癌家族中，调节表观基因组反应的基因存在遗传缺陷，这反过来又增加了乳腺癌的风险。表观基因组调控基因的这些缺陷是由单核苷酸多态性（SNP）引起的个体间DNA变异的结果，SNP改变了个体间的表观基因组过程。在这项提案中，我们将使用来自500个乳腺癌家庭的DNA，这些家庭有一个以上的乳腺癌病例。其次，我们将研究2000名乳腺癌患者和2000名健康人。通过比较两组之间表观基因组调控基因的遗传变异差异，我们将能够确定乳腺癌发展的个体遗传易感性。这项研究的结果将大大有助于疾病的早期诊断，预防和治疗，并且该提案中使用的方法可应用于鉴定易患其他癌症的基因突变，其中复杂的遗传易感性仍然未知。

DESCRIPTION (provided by applicant): Genome wide association analyses have recently discovered several low penetrant breast cancer susceptibility genes, however, vast majority of genetic predisposition to breast cancer is yet to be characterized. Considering methylation alterations in breast cancer tumors, it can be suggested that aberrant or compromised epigenome regulation may serve as a mechanism underlying predisposition to breast cancer. In this study we propose to integrate publically available data from recent GWAS and an independent candidate pathway haplotype tagging (ht) approach to identify DNA variation in epigenetic regulatory (ERG) genes that confers elevated risk to breast cancer. The panel of 989 tagging SNPs (tSNPs) capturing common genetic variation in 102 candidate epigenetic regulatory genes, will be tested in case/control association analysis separately for single effects as well as epistatic gene-gene interactions as low- penetrance breast cancer susceptibility alleles. The project will employ a two-step approach to maximize statistical power; including a cohort of cases with strong family history of breast cancer (N=500) as well as large cohorts of unselected breast cancer cases (N=2000) and healthy controls (N=2000). Cases and controls will be drawn from two populations, isolated population of Ashkenazi Jewish ancestry (AJ)(1300 case, 1000 controls) and sample population of predominantly non-AJ European ancestry (1200 cases, 1000 controls). Finally, the replication of the most significant associations will be performed on ~10,000 breast cancer cases and ~10,000 controls within Breast Cancer Association Consortium (BCAC). The proposed project will provide a first genomic approach to date utilizing systematic analysis of epigentic regulatory pathways to identify complex effects on genetic susceptibility to breast cancer. The results of this study will extend the observations from prior GWAS and may in turn provide further biological evidence elucidating a role of aberrant epigenome in breast cancer tumorigenesis. PUBLIC HEALTH RELEVANCE: Recent biotechnological advances in post-genomic era have yielded the strategies to identify genes that predispose human breast cancer. However, despite this enormous effort, for more than 70% of all hereditary breast cancers the genetic defects are yet to be identified. Human genetic information is in large extent regulated by "non-DNA" events, called epigenome. It was described that epigenome regulation is defected in many cancers, including breast tumors. We believe that in some breast cancer families there are inherited defect in genes that regulate epigenome response what in turn confers elevated risk to breast cancer. These defects in epigenome regulating genes are a result of DNA variation among individuals caused by single nucleotide polymorphisms (SNPs) what alters epigenome processes among individuals. In this proposal we will use DNA from 500 breast cancer families with more than one case of breast cancer. Second, we will look at 2000 breast cancer patients versus 2000 healthy individuals. By comparing the differences in genetic variation of epigenome regulatory genes between the two groups we will be able to determine an individual genetic predisposition for a development of breast cancer. The results of this study will significantly contribute to the early diagnosis, prevention and treatment of the disease and the methods used in this proposal can be applied to identification of gene mutations predisposing to other cancers, where complex genetic susceptibility remains unknown.