Genetic Variation Affecting Epigenome and Breast Cancer Susceptibility

描述（由申请人提供）：基因组全关联分析最近发现了一些低渗透的乳腺癌易感基因，然而，绝大多数乳腺癌的遗传易感性尚未被表征。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节可能是乳腺癌易感性的机制。在这项研究中，我们建议整合来自最近GWAS的公开数据和一个独立的候选途径单倍型标记（ht）方法来鉴定表观遗传调控（ERG）基因的DNA变异，这些基因会增加乳腺癌的风险。989个标记snp （tsnp）捕获102个候选表观遗传调控基因的共同遗传变异，将在病例/对照关联分析中分别进行单效应和上位基因-基因相互作用作为低外显率乳腺癌易感等位基因的测试。该项目将采用两步走的方法来最大限度地提高统计能力；包括一组有强烈乳腺癌家族史的病例（N=500），以及一组未选择的乳腺癌病例（N=2000）和健康对照（N=2000）。病例和对照将从两个人群中抽取：阿什肯纳兹犹太人血统（AJ）的孤立人群（1300例，1000对照）和主要是非AJ欧洲血统的样本人群（1200例，1000对照）。最后，将在乳腺癌协会联盟（breast cancer Association Consortium， BCAC）的约10,000例乳腺癌病例和约10,000例对照组中进行最显著关联的复制。该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来确定乳腺癌遗传易感性的复杂影响。本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来阐明异常表观基因组在乳腺癌肿瘤发生中的作用。

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.