Using Genomics to Reduce Breast Cancer Disparities in the African Diaspora

描述(申请人提供)：现在公认的是，与其他种族/民族相比，非洲裔美国人经历了不成比例的绝经前乳腺癌负担和更高的死亡率。最近的研究表明，非裔美国人更有可能患上三阴性乳腺癌(TNBC)，特别是基底样乳腺癌。我们最近发现，非洲裔美国人的创始群体--西非土著居民的TNBC比例甚至比非洲裔美国人更高。在尼日利亚乳腺癌研究(NBCS)的第一阶段，我们已经招募了1233名乳腺癌患者和1101名对照，另外1500名病例和种族与年龄匹配的1500名对照的招募正在进行中。此外，我们正在对非洲血统女性的乳腺癌进行全基因组关联研究，以研究乳腺癌的常见变异，结果将于2011年秋季公布。在这里，我们提出了一种高通量的全基因组DNA测序和计算生物学方法来检测罕见的、中等外显性的乳腺癌变异，并扩大了对乳腺癌基因组中种族多样性的分析。我们的具体目标是：1)从200例表型良好的病例和200名对照中提取正常血液和配对的原发乳腺肿瘤的全基因组序列，以确定三阴性乳腺癌的种系和体细胞变异。我们将通过将肿瘤中识别的变异与配对的正常血液样本和健康对照进行比较来区分遗传和体细胞变异，以评估遗传变异的病因学影响；2)在&gt；5000例乳腺癌病例和&gt；5000非洲血统和非非洲血统对照中验证选定的基因/变异。我们将首先将通过全基因组测序鉴定的稀有基因型别注入所有的GWAS样本中进行电子复制。然后，我们将在非裔美国人乳腺癌联盟中进行复制，该联盟包括黑人妇女健康研究和三阴性乳腺癌联盟。我们与包括BCAC、CIMBA和Post GWASU19在内的其他财团的联系将为复制我们的研究提供其他队列。这种综合的方法将增加我们在一个研究不足但独特的人群中识别罕见遗传变异和最具侵袭性的乳腺癌之间的联系的能力。我们的研究结果在其他人群中的复制和我们的数据共享计划将通过利用基因组学和生物技术来改善全球健康公平和减少健康差距，从而带来巨大的公共卫生利益。

DESCRIPTION (provided by applicant): It is now well recognized that African Americans experience a disproportionate burden of pre-menopausal breast cancer and higher mortality rates in comparison to other racial/ethnic groups. Recent studies demonstrate that African Americans are more likely to develop triple-negative breast cancer (TNBC) or basal- like breast cancer in particular. We recently showed that indigenous West Africans, the founder population of African Americans had even higher proportions of TNBC than do African Americans. We have recruited 1233 breast cancer cases and 1101 controls in Phase 1 of the Nigerian Breast Cancer Study (NBCS) and recruitment of additional 1500 cases and ethnicity & age-matched 1500 controls is ongoing. In addition, we are conducting a genome-wide association study (GWAS) of breast cancer in women of African Ancestry to study common variants for breast cancer and results will be available in autumn 2011. Here, we propose a high- throughput whole genome DNA sequencing and computational biology approach to examine rare, moderate- penetrance variants for breast cancers and expand the analysis of ethnic diversity in breast cancer genomes. Our specific aims are to: 1) fully sequence genomes (WGS) of normal blood and matched primary breast tumors from 200 well-phenotyped cases and 200 controls to identify germline and somatic variants for triple negative breast cancer. We will distinguish inherited from somatic variants by comparing variants identified in tumors with the paired normal blood samples and the healthy controls to evaluate the etiologic effect of the inherited variants; 2) Validate selected genes/variants in >5000 breast cancer cases and >5000 controls of African and non-African ancestry. We will first impute rare genotypes identified by whole genome sequencing into all the GWAS samples to conduct an in silico replication. Then, we will perform replication in the African American Breast Cancer Consortium, which includes Black Women's Health Study and the Triple Negative Breast Cancer Consortium. Our access to other Consortia including BCAC, CIMBA and Post GWAS U19 will provide other cohorts for replicating our studies. This integrative approach will increase our power to identify associations between rare inherited variants and the most aggressive form of breast cancer in an understudied but unique population. The replication of our study findings in other populations and our data sharing plans will bring enormous public health benefit by harnessing genomics and biotechnology to improve global health equity and reduce health disparities.