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：
9248682
负责人：
Wei Zheng
金额：
$ 80.78万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248682
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 Data Disease Epidemiologic Studies Epidemiology Ethnic group Etiology Evaluation Family Frequencies Funding Genes Genetic Genetic Predisposition to Disease Genome Genomic DNA 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 Susceptibility Gene Technology Testing Text United States Variant Woman base cancer genetics cancer risk cancer therapy case control cost cost efficient design early onset exome exome sequencing genetic linkage analysis genetic risk factor genetic variant genome sequencing genome wide association study improved insertion/deletion mutation malignant breast neoplasm new technology novel novel therapeutics

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）：遗传因素在零星和家族性乳腺癌的病因中起重要作用，这是一种复杂的多因素疾病。迄今为止确定的已知遗传危险因素，包括罕见的高隐形基因和常见的低渗透变体，仅解释了乳腺癌遗传力的28％。最近出现的证据强烈表明，大多数可遗传乳腺癌和其他复杂疾病的风险可能是由于大量低频中度渗透基因难以使用常规的基于家庭的连锁分析和全基因组范围的关联研究（GWAS）难以识别。在此应用中，我们提出了一项新的研究，以系统地搜索人类基因组中的整个编码区域，以鉴定乳腺癌的新遗传易感性因素。这项研究将建立在我们在上海妇女中进行的三项NCI资助的大型流行病学研究中建立的资源，其中从近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。具体而言，我们建议将整个外显子组对600种遗传增强的乳腺癌病例和600个对照（第1阶段）进行测序。使用第1阶段的数据以及1000个基因组项目的数据，我们将在独立的病例和对照组中选择大约350个有希望的基因，以通过变异基因分型（第2阶段）复制。从第2阶段显示有希望的关联但需要进行其他评估以确认或拒绝假设的人中，将选择大约20个基因进行第3阶段复制。据我们所知，这是使用整个外显节测序的首次大型乳腺癌研究。借助强大的方法论以及新型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，这些基因和途径将显着改善我们对乳腺癌遗传学和生物学的理解。新鉴定的基因，特别是具有很大作用大小的基因，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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women.

在中国女性中进行的基于人群的研究中乳腺癌易感基因致病突变的评估。

DOI：
10.1007/s10549-020-05643-0
发表时间：
2020
期刊：
Breast cancer research and treatment
影响因子：
3.8
作者：
Zeng,Chenjie;Guo,Xingyi;Wen,Wanqing;Shi,Jiajun;Long,Jirong;Cai,Qiuyin;Shu,Xiao-Ou;Xiang,Yongbin;Zheng,Wei
通讯作者：
Zheng,Wei

Whole-Exome Sequencing Identifies Novel Somatic Mutations in Chinese Breast Cancer Patients.

全外显子组测序鉴定出中国乳腺癌患者的新型体细胞突变。

DOI：
10.4172/1747-0862.1000183
发表时间：
2015
期刊：
Journal of molecular and genetic medicine : an international journal of biomedical research
影响因子：
0
作者：
Zhang,Yanfeng;Cai,Qiuyin;Shu,Xiao-Ou;Gao,Yu-Tang;Li,Chun;Zheng,Wei;Long,Jirong
通讯作者：
Long,Jirong