Using Genomics to Reduce Breast Cancer Disparities in the African Diaspora

描述（由申请人提供）：现在人们普遍认识到，与其他种族/族裔群体相比，非裔美国人在绝经前乳腺癌方面承受着不成比例的负担，死亡率更高。最近的研究表明，非洲裔美国人更容易患上三阴性乳腺癌（TNBC），尤其是基底样乳腺癌。我们最近发现，土著西非人，也就是非洲裔美国人的始祖比非洲裔美国人有更高的TNBC比例。我们在尼日利亚乳腺癌研究（NBCS）的第一阶段招募了1233例乳腺癌病例和1101例对照，另外招募1500例病例和种族和年龄匹配的1500例对照正在进行中。此外，我们正在进行一项非洲血统妇女乳腺癌全基因组关联研究（GWAS），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查罕见的、中等外显率的乳腺癌变异，并扩大了乳腺癌基因组的种族多样性分析。我们的具体目标是：1)从200例表型良好的病例和200例对照中提取正常血液和匹配的原发性乳腺肿瘤的全序列基因组（WGS），以鉴定三阴性乳腺癌的种系和体细胞变异。我们将通过比较肿瘤中发现的变异与配对的正常血液样本和健康对照来区分遗传变异和体细胞变异，以评估遗传变异的病因学影响；2)在5000例乳腺癌病例和5000例非洲和非非洲血统对照中验证选定的基因/变异。我们将首先将全基因组测序鉴定的稀有基因型植入所有GWAS样本中进行计算机复制。然后，我们将在非裔美国人乳腺癌联盟中进行复制，其中包括黑人妇女健康研究和三阴性乳腺癌联盟。我们对其他联盟的访问，包括BCAC， CIMBA和Post GWAS U19，将提供其他队列来复制我们的研究。这种综合方法将增加我们在研究不足但独特的人群中识别罕见遗传变异与最具侵袭性乳腺癌之间关系的能力。在其他人群中复制我们的研究结果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卫生公平和减少卫生差距，从而带来巨大的公共卫生效益。

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. PUBLIC HEALTH RELEVANCE: The primary objective of this study is to harness genomics to solve the complex problem of aggressive triple negative breast cancer (TNBC) which poses a great threat to the lives of understudied and underserved women throughout the African Diaspora. We wish to understand the etiology for TNBC in women of African ancestry and translate the knowledge into more effective management of TNBC for all women. Through this work, we hope to continue to gain insights into the mechanisms underlying racial/ethnic differences in breast cancer outcomes and develop novel approaches to reduce health inequities.