DNA Methylation Markers, Genes and Breast Cancer Risk

DNA 甲基化标记、基因和乳腺癌风险

基本信息

批准号：
10623879
负责人：
Jirong Long
金额：
$ 12.5万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-06-30
项目状态：
已结题

项目摘要

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.

概括本申请是为了响应被识别为 NOT-CA- 的特殊利益通知 (NOSI) 而提交的 22-036。家长补助金没有变化。全基因组关联研究（GWAS）已确定约 200 个与乳腺癌风险相关的基因位点的常见变异。不过翻译起来比较困难这些发现对疾病的预防和治疗有重要意义，因为致病基因和潜在机制这些基因座很大程度上是未知的。越来越多的证据表明表观遗传调控可能是因果关系遗传变异与疾病之间的途径。 DNA 甲基化是最常见和最重要的现象之一表观遗传修饰在癌症发展中起着至关重要的作用。但收集起来几乎是不可能的预诊断乳腺组织以分析大量参与者的甲基化组。在此，我们建议一种新颖的组学方法：使用遗传仪器进行全甲基化关联研究（MeWAS）。在目标 1 中，我们将利用新鲜冷冻的全基因组甲基化和遗传数据建立种族特异性预测模型乳房样本取自 600 名非洲、亚洲和欧洲血统的无癌女性（每个种族 200 名）。这些然后模型将应用于来自三个大型联盟的 GWAS 数据，包括约 123,000 个病例和欧洲约 106,000 个对照，亚洲约 25,000 个病例和约 25,000 个对照，约 20,000 个病例和约 20,000 个对照控制非洲血统来估算甲基化水平。基因预测的甲基化水平将为与乳腺癌的整体关联性以及雌激素受体和 HER2 状态进行了测试。在目标 2 中，我们将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和这些甲基化位点调节的潜在靶基因。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相关。鉴于强大的试点数据、来自三大基因联盟的独特资源，以及凭借我们团队丰富的专业知识和经验，我们拥有独特的优势来开展该项目。研究结果将极大地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学发现转化为预防和治疗。