DNA Methylation Markers, Genes and Breast Cancer Risk

总结 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 22-036.父母补助金没有变化。全基因组关联研究（GWAS）已经确定 与乳腺癌风险相关的约200个遗传基因座的常见变异。但是，翻译起来很难 这些发现对疾病的预防和治疗，因为致病基因和潜在的机制， 这些基因座在很大程度上是未知的。越来越多的证据表明，表观遗传调节可能是因果关系， 遗传变异与疾病之间的联系。DNA甲基化是人类最常见和最重要的 表观遗传修饰在癌症发展中起着关键作用。但是，要想收集几乎不可能 诊断前乳腺组织，以分析来自大量参与者的甲基化组。在此，我们建议 一种新的组学方法：使用遗传仪器的全甲基化关联研究（MeWAS）。在目标1中， 我们将建立种族特异性预测模型，使用基因组范围内的甲基化和新鲜冷冻的遗传数据， 来自非洲、亚洲和欧洲血统的600名无癌症妇女的乳房样本（每个种族200名）。这些 然后将模型应用于来自三个大型联盟的GWAS数据，包括约123，000例病例， 约106，000例欧洲对照，约25，000例亚洲对照，约20，000例亚洲对照，约20，000例亚洲对照 非洲血统的对照来估算甲基化水平。基因预测的甲基化水平将是 通过雌激素受体和HER2状态检测与乳腺癌的总体相关性。在目标2中，我们 进行一系列综合功能分析以评估有希望的甲基化位点的功能， 由这些甲基化位点调控的潜在靶基因。在目标3中，我们将选择前20个甲基化 用于体外功能测定的位点及其靶基因，以评估其对主要细胞功能的影响 与癌症生物学有关。鉴于强大的试点数据，来自三个大型遗传财团的独特资源， 凭借我们团队的广泛专业知识和经验，我们在开展该项目方面处于独特的地位。这些发现 将大大提高我们对乳腺癌发病机制的遗传和生物学基础的理解， 促进将遗传发现转化为预防和治疗。

Summary This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-036. There is no change for the parent grant. Genome-wide association studies (GWAS) have identified common variants in ~200 genetic loci associated with breast cancer risk. However, it is difficult to translate these findings to disease prevention and treatment because causal genes and underlying mechanisms in these loci are largely unknown. Increasing evidence suggests that epigenetic regulation may be on the causal pathway between genetic variants and diseases. DNA methylation, one of the most frequent and important epigenetic modifications, plays a crucial role in cancer development. However, it is almost impossible to collect pre-diagnostic breast tissues to profile the methylome from a large number of participants. Herein, we propose a novel -omics approach: a methylation-wide association study (MeWAS) using genetic instruments. In Aim 1, we will build race-specific prediction models using genome wide methylation and genetic data in fresh-frozen breast samples from 600 cancer-free women of African-, Asian- and European- ancestry (200 per race). These models will then be applied to the GWAS data from three large consortia, including ~123,000 cases and ~106,000 controls of European, ~25,000 cases and ~25,000 controls of Asian-, ~20,000 cases and ~20,000 controls of African- ancestry to impute methylation levels. The genetically predicted methylation levels will be tested in association with breast cancer overall and by estrogen receptor and HER2 status. In Aim 2, we will perform a series of integrative functional analyses to evaluate the functions of promising methylation sites and the potential target genes regulated by these methylation sites. In Aim 3, we will select the top 20 methylation sites and their target genes for in vitro functional assays to assess their influence on major cell functions related to cancer biology. Given the strong pilot data, unique resources from three large genetic consortia, and our team's extensive expertise and experience, we are uniquely positioned to conduct this project. The findings will greatly improve our understanding of the genetic and biological basis of breast cancer pathogenesis and facilitate the translation of genetic findings to prevention and treatment.