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.
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.
|Rebbeck, Timothy R (see original citation for additional authors) (2018) Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat 39:593-620|
|Wang, Shengfeng; Qian, Frank; Zheng, Yonglan et al. (2018) Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry. Breast Cancer Res Treat 168:703-712|
|Wang, Shengfeng; Huo, Dezheng; Kupfer, Sonia et al. (2018) Genetic variation in the vitamin D related pathway and breast cancer risk in women of African ancestry in the root consortium. Int J Cancer 142:36-43|
|Zheng, Yonglan; Walsh, Tom; Gulsuner, Suleyman et al. (2018) Inherited Breast Cancer in Nigerian Women. J Clin Oncol 36:2820-2825|
|Wang, Shengfeng; Ogundiran, Temidayo; Ademola, Adeyinka et al. (2018) Development of a Breast Cancer Risk Prediction Model for Women in Nigeria. Cancer Epidemiol Biomarkers Prev 27:636-643|
|Wang, Jiebiao; Liu, Qianying; Pierce, Brandon L et al. (2018) A meta-analysis approach with filtering for identifying gene-level gene-environment interactions. Genet Epidemiol 42:434-446|
|Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B et al. (2017) Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3. Breast Cancer Res Treat 161:117-134|
|Milne, Roger L (see original citation for additional authors) (2017) Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet 49:1767-1778|
|Johnston, Henry Richard; Hu, Yi-Juan; Gao, Jingjing et al. (2017) Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome. Sci Rep 7:46398|
|Huo, Dezheng; Hu, Hai; Rhie, Suhn K et al. (2017) Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas. JAMA Oncol 3:1654-1662|
Showing the most recent 10 out of 24 publications