A profile of inherited predisposition to breast cancer among Nigerian women. Y. Zheng1, T. Walsh2, F. Yoshimatsu1, M. Lee2, S. Gulsuner2, S. Casadei2, A. Rodriguez3, T. Ogundiran4, C. Babalola5, O. Ojengbede6, D. Sighoko1, R. Madduri3, M.-C. King2, O. Olopade1 1) Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, USA; 2) Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; 3) Computation Institute, The University of Chicago, Chicago, IL, USA; 4) Department of Surgery, University of Ibadan, Ibadan, Oyo, Nigeria; 5) Institute for Advanced Medical Research and Training, College of Medicine & Faculty of Pharmacy, University of Ibadan, Ibadan, Oyo, Nigeria; 6) Centre for Population & Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria.

   Women of the African Diaspora disproportionately experience early-onset, hormone-receptor negative, aggressive breast cancer. This burden may be due at least in part to differences in the distribution of inherited mutations in breast cancer genes. But little is known about inherited mutations among African women with breast cancer. To obtain a comprehensive mutational profile, we are using the targeted capture and multiplex sequencing panel, BROCA to evaluate known and emerging breast cancer genes in genomic DNA of 1000 breast cancer patients and 1000 female controls from Ibadan, Nigeria; 400 cases and 400 controls have been sequenced thus far. Our analysis includes nonsense and frameshift mutations, gene-disrupting CNVs, missenses if experimentally established as damaging, and mutations at highly conserved sites (GERP>5.0) that are predicted by at least two in silico tools to disrupt splicing. The mutational profile of the Nigerian patients is strikingly different than mutational profiles of patients of other ancestries. Of the 400 Nigerian patients, 73 (18%) carry a mutation in any of 10 different genes: 43 in BRCA1, 18 in BRCA2, 3 in PALB2, 2 each in BRIP1, RAD51C, and TP53, and 1 each in CHEK2, CHEK1, GEN1, and NBN. One patient carries both BRCA2 and BRIP1 mutations. This profile is distinctive in that BRCA1 and BRCA2 represent more of the mutational burden compared to other genes, PALB2 is a relatively minor contributor, CHEK2 is a very minor contributor, and ATM is completely absent. At the allelic level, the Nigerian profile is highly heterogeneous: the 43 BRCA1 patients carry 27 different mutations and the 18 BRCA2 patients carry 16 different mutations. Furthermore, 10 mutations (8 in BRCA1 or BRCA2), at completely conserved sites with very high GERP scores, were predicted to disrupt splicing. Most of these mutations were new to us, represent a higher rate of splice mutations than we have observed in any other population, and call for experimental assessment. Of the 400 controls, 9 (2%) carried a mutation in 7 genes: 2 in BRCA1 (ages 35 and 45), 2 in BRCA2 (ages 39 and 40) and 1 each in BARD1, ATR, FAM175A, MRE11A, and SLX4. Relative risks were 21.5 (95% CI [5.2, 88,2]) for BRCA1 and 9.0 (95% CI [2.1, 38.5]) for BRCA2. To understand the burden of aggressive breast cancer among women of African ancestry will require comprehensive comparative genetic and clinical analysis of large cohorts of patients. This profile is intended as a beginning.

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