Genetic Susceptibility for Breast Cancer Subtypes

我们建议使用联合应用发现乳腺癌遗传易感性的新标记。 四个正在进行的关于非裔美国妇女的大型流行病学研究的资源。我们的协作 包括卡罗莱纳乳腺癌研究，妇女健康圈研究，黑人妇女健康研究， 以及多种族群体。总共5534名非裔美国人病例和5534名对照的DNA样本 将可用于分析，以及来自病例的面对面采访数据和肿瘤块。三 提出了研究途径：(1)密集基因分型和精细定位 乳腺癌和相关候选基因的全基因组关联研究(GWAS)，具有特定的 重点是精细绘制与非裔美国妇女相关的基因座图。包括在精细映射中的是一个独特的 在染色体5q31上我们最近在非洲裔美国妇女中发现了；(2)发现 利用靶向DNA重测序和基于基因表达的方法寻找潜在的功能等位基因； 旨在确定乳腺癌病例亚组的遗传风险因素的统计分析 发病年龄和肿瘤生物学(ER状态和固有亚型：基底样、腔A、腔B、 HER2+/ER-)。四项流行病学研究的综合资源将有助于识别高危人群 等位基因和单倍型，允许快速复制发现，并产生更准确的影响估计 乳腺癌亚组。基因分型和其他实验室研究将与 Biosecimen核心、招募和招募更多研究参与者将通过数据进行 收集核心，并将与生物统计和数据合作进行统计分析 管理核心。来自项目1的基因数据将与项目2、3和4一起使用，以 开发包含可修改的遗传标记的乳腺癌易感性的复杂模型 环境风险因素和乳腺癌肿瘤亚型是不同的疾病结局。

We propose to discover novel markers of genetic susceptibility for breast cancer using the combined resources of four large on-going epidemiologic studies of African American women. Our collaboration includes the Carolina Breast Cancer Study, Women's Circle of Health Study, Black Women's Health Study, and the Multiethnic Cohort. DNA samples from a total of 5534 African American cases and 5534 controls will be available for analysis, along with in-person interview data and tumor blocks from cases. Three avenues of investigation are proposed: (1) Dense genotyping and fine-mapping of loci identified in previous genome-wide association studies (GWAS) of breast cancer and related candidate genes, with a particular focus on fine-mapping of loci relevant to African American women. Included in the fine-mapping is a unique locus on chromosome 5q31 we recently identified in a GWAS of African American women; (2) Discovery of potential functional alleles using targeted DNA resequencing and gene expression-based approaches; (3) Statistical analyses aimed at identifying genetic risk factors for subgroups of breast cancer cases defined by early age at onset and tumor biology (ER status and intrinsic subtypes: basal-like, luminal A, luminal B, HER2+/ER-). The combined resources of four epidemiologic studies will facilitate identification of at-risk alleles and haplotypes, permit rapid replication of findings, and produce more precise estimates of effect for breast cancer subgroups. Genotyping and other laboratory studies will be conducted in cooperation with the Biospecimen Core, recruitment and enrollment of additional study participants will be undertaken by the Data Collection Core, and statistical analyses will be conducted in cooperation with the Biostatistics and Data Management Core. Genotype data from Project 1 will be used in conjunction with Projects 2, 3 and 4 to develop complex models for breast cancer susceptibility that incorporate genetic markers, modifiable environmental risk factors, and breast cancer tumor subtypes as distinct disease outcomes.