Genetic Susceptibility for Breast Cancer Subtypes

我们建议使用联合的方法来发现乳腺癌遗传易感性的新标志物。 四个大型的非裔美国妇女正在进行的流行病学研究的资源。我们的合作 包括卡罗莱纳乳腺癌研究，妇女健康研究圈，黑人妇女健康研究， 和多民族群体来自5534例非裔美国人病例和5534例对照的DNA样本 将可用于分析，沿着亲自采访数据和病例的肿瘤块。三 研究的途径提出：（1）密集的基因分型和精细定位的位点确定在以前的 乳腺癌和相关候选基因的全基因组关联研究（GWAS）， 专注于与非洲裔美国妇女相关的基因位点的精细映射。精细映射中包含一个唯一的 我们最近在非裔美国女性的GWAS中发现了染色体5 q31上的基因座;（2）发现 使用靶向DNA重测序和基于基因表达的方法的潜在功能等位基因;（3） 统计分析旨在确定乳腺癌病例亚组的遗传风险因素， 早期发病年龄和肿瘤生物学（ER状态和内在亚型：基底样，管腔A，管腔B， HER2+/ER-）。四项流行病学研究的综合资源将有助于识别 等位基因和单倍型，允许快速复制的结果，并产生更精确的估计效果， 乳腺癌亚组。基因分型和其他实验室研究将与 生物样本核心、招募和入组其他研究受试者将由数据中心负责 将与生物统计和数据中心合作进行收集核心和统计分析。 管理核心。项目1的基因型数据将与项目2、3和4结合使用， 开发乳腺癌易感性的复杂模型，包括遗传标记，可修改的 环境风险因素和乳腺癌肿瘤亚型作为不同的疾病结局。

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.