Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium

非洲血统（AA）女性比欧洲血统（EA）女性更有可能在45岁之前被诊断患有乳腺癌，并且具有更具侵袭性的肿瘤，其特征在于高级别，雌激素和孕酮受体和HER-2（三阴性）呈阴性染色。他们也更有可能患有基底样乳腺肿瘤，这是一种预后最差的内在乳腺癌亚型。这些差异的原因尚不清楚，现有的研究缺乏统计能力来调查年轻女性乳腺癌亚型的风险因素。在本计划项目中，我们将汇集来自卡罗莱纳乳腺癌研究（CBCS）、黑人妇女健康研究（BWHS）、妇女健康研究圈（WCHS）和多种族队列（MEC）的数据和样本，并继续累积病例，最终样本量超过5500例病例和5500例对照。我们将收集组织块并根据其内在亚型对癌症进行分类，并在四个高度互动的项目中调查亚型的特定遗传，生物和流行病学风险因素。具体目标是检查诊断时的年龄和乳腺癌亚型之间的关联，以及1）最近GWAS发现中确定的遗传基因座，使用精细定位来确定潜在的致病等位基因; 2）妊娠史和哺乳，以及相关途径中遗传变异的潜在修饰; 3）体型，早期生活和成年体力活动，以及基因/环境相互作用;（4）在非洲可能适应地方性传染病（强免疫反应）和强烈阳光（高皮肤色素沉着）的危险因素，但在西方社会可能导致炎症环境和维生素D缺乏，这可能与早期侵袭性乳腺癌有关。互动的目标将调查亚型和遗传和生物因素之间的关系，以及流行病学特征。支持所有项目的核心包括：1）行政核心; 2）数据收集核心; 3）生物标本核心; 4）生物统计和数据管理核心。通过汇集我们的数据，标本，重要的是，专门知识来调查这些假设，我们将阐明AA妇女侵袭性，早发性乳腺癌的病因。

Women of African ancestry (AA) women are more likely than those with European ancestry (EA) to be diagnosed with breast cancer before age 45, and to have more aggressive tumors, characterized by high grade, with negative staining for estrogen and progesterone receptors and HER-2 (triple negative). They are also more likely to have basal-like breast tumors, an intrinsic breast cancer subtype with the poorest prognosis. The reasons for these disparities are unclear, and existing studies lack the statistical power to investigate risk factors for breast cancer subtypes among young women. In this Program Project, we will pool data and samples from the Carolina Breast Cancer Study (CBCS), the Black Women's Health Study (BWHS), the Women's Circle of Health Study (WCHS) and the Multi-ethnic Cohort (MEC) and continue to accrue cases for a final sample size of more than 5500 cases and 5500 controls. We will collect tissue blocks and classify cancers by their intrinsic subtypes, and investigate specific genetic, biologic and epidemiologic risk factors for subtypes in four highly interactive projects. The specific aims are to examine associations between age at diagnosis and breast cancer subtypes and 1) genetic loci identified in recent GWAS findings, using fine-mapping to identify potential causal alleles; 2) pregnancy history and lactation, and potential modification by genetic variants in related pathways; 3) body size, early life and adult physical activity, and gene/environment interactions; and 4) risk factors that may have been adaptive in Africa to endemic infectious disease (robust immune response) and intense sunlight (high skin pigmentation), but that in western society may result in hyper-inflammatory milieu and vitamin D deficiency, which may be related to early, aggressive breast cancer. Interactive aims will investigate relationships between subtypes and genetic and biologic factors, as well as epidemiologic characteristics. Cores that support all of the projects include the 1) Administrative Core; 2) Data Collection Core; 3) Biospecimen Core; and 4) Biostatistics and Data Management Core. By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women.