Genome Sequencing to identify novel genetic factors for breast cancer risk

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，这是一种复杂的多因素疾病。迄今为止，已知的遗传风险因素，包括罕见的高外显基因和常见的低外显基因变异，只能解释约28%的乳腺癌遗传率。最近出现的证据有力地表明，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，这些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，以确定新的乳腺癌遗传易感性因素。本研究将建立在我们在上海进行的三个nci资助的大型流行病学研究中建立的资源基础上，这些研究收集了近8000例乳腺癌病例和大量社区对照的基因组DNA样本和综合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（第一阶段）的整个外显子组进行测序。利用第一阶段和1000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（第二阶段）选择大约350个有希望的基因进行复制。大约20个基因将从那些在第二阶段显示出有希望的关联，但需要额外的评估来确认或拒绝假设的基因中选择用于第三阶段的复制。据我们所知，这是首次使用全外显子组测序对乳腺癌进行的大型关联研究。通过强有力的方法和新技术的使用和研究设计，该研究将确定新的基因和途径，这将显著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。

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.