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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要遗传因素在散发性和家族性乳腺癌的病因学中发挥着重要作用。自 2007 年以来，已在全基因组中鉴定出约 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，往往很难将 GWAS 研究结果转化为疾病预防和治疗，因为大大多数 GWAS 识别的基因座是未知的。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% 的疾病具有遗传性可以通过调节基因表达的遗传变异来解释。在此，我们提出三点建议强有力的全转录组关联研究（TWAS）系统地研究乳腺癌风险与非洲人转录组基因表达的关联，亚洲和欧洲的后裔。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测定并建立种族特异性基因表达使用 1000 名非洲、亚洲和欧洲血统女性的数据建立预测模型。这些模型将应用于约 320,000 个乳腺癌生成的 GWAS 数据患者和对照估算基因表达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 状态有关。瞄准 2、我们将选择Aim 1中确定的前50个基因进行体外功能测定，以评估其对与癌症生物学相关的主要细胞功能的影响。在目标 3 中，我们将评估是否 TWAS 鉴定的基因在正常乳腺组织和乳腺癌中可能表达不同从非洲、亚洲和欧洲后裔收集的组织来评估这些是否基因可能通过分子亚型导致乳腺癌风险的种族差异。和强有力的方法论和大样本量，我们认为这项拟议的研究应该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极大提高人们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患者护理。