Integrating genomic and transcriptomic data to identify breast cancer susceptibility genes

整合基因组和转录组数据来识别乳腺癌易感基因

• 批准号: 10197851
• 负责人: Jirong Long
• 金额: $ 20.02万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197851
• 关键词: ABCC1 gene; African; Asia; Asians; Bioinformatics; Biological; Biological Assay; Biological Process; Breast Cancer Genetics; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer gene; Cancer Biology; Cancer Control; Cancer-Predisposing Gene; Candidate Disease Gene; Cell physiology; Complex; Data; Disease; Disease susceptibility; ERBB2 gene; Estrogen Receptors; Etiology; European; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic Risk; Genetic Translation; Genetic study; Genome; Genomics; Genotype; Genotype-Tissue Expression Project; Hereditary Breast Carcinoma; Heritability; In Vitro; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Methodology; Modeling; Patient Care; Phenotype; Pilot Projects; Play; Race; Risk; Role; Sample Size; Sampling; Testing; The Cancer Genome Atlas; Tissue Sample; Tissues; Translating; Tumor Tissue; Woman; base; cancer genetics; cancer risk; case control; causal variant; cost; cost efficient; density; disorder prevention; disorder risk; genetic variant; genome sequencing; genome wide association study; genomic data; improved; in vitro Assay; malignant breast neoplasm; molecular subtypes; novel; novel strategies; predictive modeling; racial difference; risk variant; trait; transcriptome; transcriptome sequencing; transcriptomics; whole genome

Project Summary Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. Since 2007, common genetic variants in ~200 loci have been identified in genome-wide association studies (GWAS) in relation to breast cancer risk. However, it is often difficult to translate GWAS findings to disease prevention and treatment since causal genes in the large majority of GWAS-identified loci are unknown. Furthermore, a large fraction of breast cancer heritability remains unexplained. Recent studies suggest that nearly 80% of disease heritability can be explained by genetic variants regulating gene expression. Herein, we propose three well-powered transcriptome-wide association studies (TWAS) to systematically investigate the association of breast cancer risk with gene expression across the transcriptome of African, Asian and European descendants. In Aim 1, we will perform RNA sequencing and high-density genotyping assays using normal breast tissue samples and build race-specific gene expression prediction models using data from 1000 women of African, Asian and European descent. These models will be applied to the GWAS data generated from approximately 320,000 breast cancer patients and controls to impute gene expression for association analyses of predicted gene expression with risk of breast cancer overall and by estrogen receptor and HER2 status. In Aim 2, we will select the top 50 genes identified in Aim 1 for in vitro functional assays to assess their influence on major cell functions related to cancer biology. In Aim 3, we will evaluate whether TWAS-identified genes may express differently in normal breast tissues and breast cancer tissues collected from African, Asian, and European descendants to assess whether these genes may contribute to racial differences in breast cancer risk by molecular subtypes. With strong methodology and a large sample size, we believe that this proposed study should be able to identify and characterize a large number of novel genes related to breast cancer risk. Uncovering breast cancer susceptibility genes will greatly improve the understanding of the genetic and biological basis for breast cancer and accelerate the translation of genetic findings to disease prevention and patient care.

项目摘要 遗传因素在散发性和家族性乳腺癌的病因学中起重要作用。 自2007年以来，在全基因组范围内已经确定了约200个基因座的常见遗传变异。 与乳腺癌风险相关的关联研究（GWAS）。然而，通常很难 将GWAS的发现转化为疾病的预防和治疗，因为大规模的致病基因 大多数GWAS鉴定的基因座是未知的。此外，很大一部分乳腺癌 遗传性仍然无法解释。最近的研究表明，近80%的疾病遗传性 可以通过调节基因表达的遗传变异来解释。在此，我们提出三个 强有力的全转录组关联研究（TWAS）系统地研究了 乳腺癌风险与非洲人转录组基因表达的关联， 亚洲和欧洲后裔。在目标1中，我们将进行RNA测序和高密度 使用正常乳腺组织样本进行基因分型检测，并建立种族特异性基因表达 使用来自非洲，亚洲和欧洲血统的1000名妇女的数据预测模型。这些 模型将应用于从大约320，000例乳腺癌中生成的GWAS数据， 对患者和对照进行基因表达的估算，以进行预测基因的关联分析 表达与乳腺癌总体风险以及雌激素受体和HER2状态的关系。在Aim中 2，我们将选择在目标1中鉴定的前50个基因进行体外功能测定，以评估它们的功能。 影响与癌症生物学相关的主要细胞功能。在目标3中，我们将评估 TWAS鉴定的基因可能在正常乳腺组织和乳腺癌中表达不同 从非洲人、亚洲人和欧洲人的后代身上收集的组织，以评估这些组织是否 基因可能导致乳腺癌风险的分子亚型的种族差异。与 强大的方法和大样本量，我们认为这项拟议的研究应该是 能够识别和表征大量与乳腺癌风险相关的新基因。 揭示乳腺癌易感基因将大大提高对乳腺癌的认识。 乳腺癌的遗传和生物学基础，并加速遗传发现的转化 疾病预防和病人护理。