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

• 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
• 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

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的病因学中起重要作用，乳腺癌是一种复杂的多因素疾病。迄今为止，已知的遗传风险因素，包括罕见的高等位基因和常见的低等位基因变异，只能解释乳腺癌遗传率的28%。最近出现的证据有力地表明，大多数乳腺癌和其他复杂疾病的遗传风险可能是由于大量的低频率中度突变基因，这些基因很难使用传统的基于家族的连锁分析和全基因组关联研究（GWAS）来识别。在这项应用中，我们提出了一项新的研究，系统地搜索人类基因组中的整个编码区，以确定乳腺癌的新的遗传易感因素。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基础上，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样本和全面的临床和流行病学数据。具体来说，我们建议对600例基因富集的乳腺癌病例和600例对照（第1阶段）的整个外显子组进行测序。利用第1阶段和1000个基因组计划的数据，我们将在一组独立的病例和对照中通过变异基因分型（第2阶段）选择大约350个有希望的基因进行复制。将从那些在第2阶段显示有希望关联但需要额外评估以确认或拒绝假设的基因中选择约20个基因用于第3阶段复制。据我们所知，这是第一个使用全外显子组测序的乳腺癌大关联研究。凭借强大的方法学和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，这将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，特别是那些具有显著效应大小的基因，可以作为新型癌症治疗的靶点，并用于癌症筛查和风险评估。

项目成果

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
• 作者: Zhang,Yanfeng;Cai,Qiuyin;Shu,Xiao-Ou;Gao,Yu-Tang;Li,Chun;Zheng,Wei;Long,Jirong
• 通讯作者: Long,Jirong