Genome Sequencing to identify novel genetic factors for breast cancer risk

基因组测序识别乳腺癌风险的新遗传因素

基本信息

批准号：
8468665
负责人：
Wei Zheng
金额：
$ 84.34万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-10 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468665
关键词：
Asians BRCA1 gene Bioinformatics Breast Cancer Genetics Breast Cancer Prevention Breast Cancer Risk Factor Cancer Biology Cancer-Predisposing Gene Candidate Disease Gene Chinese People Clinical Code Communities Complex DNA Data Disease Epidemiologic Studies Epidemiology Ethnic group Etiology Evaluation Family Frequencies Funding Genes Genetic Genetic Predisposition to Disease Genetic Variation Genome Genomics Genotype Hereditary Breast Carcinoma Heritability High Risk Woman Human Genome Investigation Malignant Neoplasms Methodology Pathway interactions Penetrance Phase Play Population Predisposition Prevention strategy Recruitment Activity Research Design Resources Risk Risk Assessment Role Sampling Screening for cancer Staging Technology Testing Text United States Variant Woman base cancer genetics cancer risk cancer therapy case control cost design early onset exome exome sequencing genetic linkage analysis genetic risk factor genetic variant genome sequencing genome wide association study improved malignant breast neoplasm new technology novel

项目摘要

DESCRIPTION (provided by applicant): Genetic factors play an important role in the etiology of both sporadic and familial breast cancer, a complex, multifactorial disease. Known genetic risk factors identified to date, including both rare high- penetrance genes and common low-penetrance variants, explain only about 28% of heritability for breast cancer. Recently emerged evidence strongly suggests that most of the heritable risk for breast cancer and other complex diseases may be due to a large number of low-frequency moderate-penetrance genes that are difficult to identify using conventional family-based linkage analyses and genome-wide association studies (GWAS). In this application, we propose a novel study to systematically search for the entire coding region in the human genome to identify new genetic susceptibility factors for breast cancer. This study will be built upon the resources we established in three NCI-funded large epidemiologic studies conducted among women in Shanghai, in which genomic DNA samples and comprehensive clinical and epidemiological data were collected from nearly 8,000 breast cancer cases and a large number of community controls. Specifically, we propose to sequence the whole exome for 600 genetically-enriched breast cancer cases and 600 controls (Stage 1). Using data from Stage 1 and those from the 1000 Genomes Project, we will select approximately 350 promising genes for replication through variant genotyping (Stage 2) in an independent set of cases and controls. Approximately 20 genes will be selected for Stage 3 replication from those that show promising association in Stage 2 but require additional evaluation to either confirm or reject the hypotheses. To our knowledge, this is the first large association study for breast cancer using whole exome sequencing. With strong methodology and the use of novel technology and study design, the proposed study will identify novel genes and pathways that will significantly improve our understanding of breast cancer genetics and biology. Newly identified genes, particularly those with a substantial effect size, could serve as targets for novel cancer treatment and be used for cancer screening and risk assessment.

描述（由申请人提供）：遗传因素在散发性和家族性乳腺癌这一复杂的多因素疾病的病因学中发挥着重要作用。迄今为止确定的已知遗传风险因素，包括罕见的高外显率基因和常见的低外显率变异，只能解释约 28% 的乳腺癌遗传性。最近出现的证据强烈表明，乳腺癌和其他复杂疾病的大部分遗传风险可能是由于大量低频中等外显率基因难以使用传统的基于家族的连锁分析和全基因组关联来识别。研究（GWAS）。在此应用中，我们提出了一项新颖的研究，系统地搜索人类基因组中的整个编码区，以识别乳腺癌的新遗传易感因素。这项研究将建立在我们在上海女性中进行的三项 NCI 资助的大型流行病学研究中建立的资源的基础上，这些研究从近 8,000 例乳腺癌病例和大量社区对照中收集了基因组 DNA 样本以及全面的临床和流行病学数据。具体来说，我们建议对 600 个基因富集的乳腺癌病例和 600 个对照的整个外显子组进行测序（第一阶段）。利用第一阶段和千基因组计划的数据，我们将选择大约 350 个有希望的基因，通过变异基因分型（第二阶段）在一组独立的病例和对照中进行复制。从那些在第 2 阶段表现出有希望关联但需要额外评估以确认或拒绝假设的基因中，将选择大约 20 个基因进行第 3 阶段复制。据我们所知，这是第一个使用全外显子组测序进行乳腺癌的大型关联研究。凭借强大的方法论以及新技术和研究设计的使用，拟议的研究将确定新的基因和途径，从而显着提高我们对乳腺癌遗传学和生物学的理解。新发现的基因，特别是那些具有显着效应的基因，可以作为新型癌症治疗的靶标，并用于癌症筛查和风险评估。