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.

项目摘要遗传因素在零星和家族性乳腺癌的病因中起重要作用。自2007年以来，在全基因组中已经鉴定出约200个基因座的常见遗传变异与乳腺癌风险有关的协会研究（GWAS）。但是，通常很难将GWA的发现转化为预防疾病和治疗，因为较大的因果基因大多数GWAS识别的基因座都是未知的。此外，很大一部分乳腺癌遗传力仍然无法解释。最近的研究表明，将近80％的疾病遗传力可以通过调节基因表达的遗传变异来解释。在这里，我们提出了三个驱动良好的全转录组关联研究（TWA），系统地研究乳腺癌风险与非洲转录组中的基因表达相关，亚洲和欧洲后代。在AIM 1中，我们将执行RNA测序和高密度使用正常乳腺组织样品并建立种族特异性基因表达的基因分型测定使用来自非洲，亚洲和欧洲血统的1000名女性的数据进行预测模型。这些模型将应用于大约320,000个乳腺癌产生的GWAS数据患者和对照将基因表达赋予预测基因的缔合分析具有总体乳腺癌和雌激素受体和HER2状态的风险的表达。目标 2，我们将选择AIM 1中标识的前50个基因以评估其体外功能测定对与癌症生物学有关的主要细胞功能的影响。在AIM 3中，我们将评估是否在正常的乳腺组织和乳腺癌中，Twas识别的基因表达不同从非洲，亚洲和欧洲后代收集的组织来评估这些是否是否基因可能会导致分子亚型的乳腺癌风险种族差异。和强大的方法论和大型样本量，我们认为这项拟议的研究应该是能够识别和表征与乳腺癌风险有关的大量新基因。发现乳腺癌的易感性基因将大大提高对乳腺癌的遗传和生物学基础，并加速遗传发现的翻译预防疾病和患者护理。