DNA Methylation Markers, Genes and Breast Cancer Risk

DNA 甲基化标记、基因和乳腺癌风险

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10623879
• 关键词: African; African ancestry; Asian; Biological; Biological Assay; Breast; Breast Cancer Risk Factor; Cancer Biology; Cell physiology; DNA Methylation; Data; Development; Diagnostic; ERBB2 gene; Epigenetic Process; Estrogen Receptors; European; Freezing; Genes; Genetic; Genetic Diseases; Genetic Translation; In Vitro; Malignant Neoplasms; Mammary Gland Parenchyma; Methylation; Modeling; Modification; Participant; Pathogenesis; Pathway interactions; Play; Positioning Attribute; Prevention; Race; Resources; Role; Sampling; Series; Site; Testing; Translating; Variant; Woman; causal variant; disorder prevention; epigenetic regulation; experience; genetic variant; genome wide association study; genome wide methylation; genomic locus; improved; instrument; interest; malignant breast neoplasm; methylation biomarker; methylome; novel; parent grant; predictive modeling; response

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 该申请是为了响应特殊利益通知（NOSI）而提交 22-036。父母赠款没有更改。全基因组关联研究（GWAS）已经鉴定 与乳腺癌风险相关的约200个遗传基因座的常见变体。但是，很难翻译 这些发现预防疾病和治疗的结果是因为因果基因和基本机制 这些基因座在很大程度上未知。越来越多的证据表明表观遗传调节可能是在因果 遗传变异和疾病之间的途径。 DNA甲基化，最常见，最重要的之一 表观遗传修饰在癌症发展中起着至关重要的作用。但是，几乎不可能收集 诊断前的乳房组织介绍了大量参与者的甲基化合物。在这里，我们建议 一种新颖的方法方法：使用遗传仪器的甲基化范围协会研究（MEWAS）。在AIM 1中， 我们将使用基因组广泛的甲基化和新鲜冻干中的遗传数据构建种族特异性的预测模型 来自非洲，亚洲和欧洲血统的600名无癌女性的乳房样本（每场比赛200）。这些 然后，模型将应用于来自三个大财团的GWAS数据，包括约123,000个案件和 〜106,000个欧洲控制，约25,000例和约25,000个亚洲人，约20,000案例和约20,000例 对非洲血统的控制归为甲基化水平。遗传预测的甲基化水平将是 与整体乳腺癌和雌激素受体和HER2状态进行了测试。在AIM 2中，我们将 执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AIM 3中，我们将选择前20个甲基化 位点及其目标基因用于体外功能测定，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，来自三个大遗传联盟的独特资源，以及 我们团队丰富的专业知识和经验，我们在进行这个项目方面拥有独特的位置。发现 将大大提高我们对乳腺癌发病机理的遗传和生物学基础的理解和 促进将遗传发现转化为预防和治疗。