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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01CA161032-02S1
Application #
8932976
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Ogunbiyi, Peter
Project Start
2012-07-19
Project End
2015-12-31
Budget Start
2014-07-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$35,744
Indirect Cost
$13,121
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
(2016) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat Commun 7:12675
Guindalini, Rodrigo Santa Cruz; Song, Andrew; Fackenthal, James D et al. (2016) Genetic anticipation in BRCA1/BRCA2 families after controlling for ascertainment bias and cohort effect. Cancer 122:1913-20
(2016) No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer. Gynecol Oncol 141:386-401
Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B et al. (2016) 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 :
(2016) Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. Breast Cancer Res 18:64
Adedokun, Babatunde O; Olopade, Christopher O; Olopade, Olufunmilayo I (2016) Building local capacity for genomics research in Africa: recommendations from analysis of publications in Sub-Saharan Africa from 2004 to 2013. Glob Health Action 9:31026
Kessler, Michael D; Yerges-Armstrong, Laura; Taub, Margaret A et al. (2016) Challenges and disparities in the application of personalized genomic medicine to populations with African ancestry. Nat Commun 7:12521
Mathias, Rasika Ann; Taub, Margaret A; Gignoux, Christopher R et al. (2016) A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun 7:12522
Baretta, Zora; Mocellin, Simone; Goldin, Elena et al. (2016) Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis. Medicine (Baltimore) 95:e4975
Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie et al. (2016) Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2. Breast Cancer Res 18:15

Showing the most recent 10 out of 15 publications