Objectives: Paucity of data on populations of African Ancestry in clinical trials continues to limit our ability to design and implement innovative solutions to narrow the breast cancer survival gap amongst Africans, African Americans, and European Americans. We have developed a cross-continent research infrastructure to examine the spectrum of genomic alterations in breast tumors from West Africa and subsequently, to compare them to tumors from African American women and women of European Ancestry in The Cancer Genome Atlas (TCGA) database. Methods: Consecutive women with breast cancer presenting for treatment at the University College Hospital, Ibadan and at Lagos State University Teaching Hospital, Lagos, Nigeria gave informed consent and were recruited to the West African Breast Cancer Study (WABCS) between 2013-2016. Tumor-normal pairs were subjected to exome and/or high-depth (90x) genome sequencing. High confidence somatic mutations (substitutions, insertions/deletions and structural variants) were obtained by using multiple variant callers. Furthermore, 1,089 exomic and 80 genomic breast tumor-normal pairs from TCGA were harmonized with WABCS samples, resulting in a cohort of 147 West Africans (147 exome; 40 genome), 154 African Americans (154 exome; 31 genome), and 776 Caucasians (776 exome; 43 genome). Results: Across the exomes, genes commonly altered in breast cancer in TCGA are also altered in women of African ancestry, but the mutational spectrum is quite different, demonstrating overrepresentation of tumors with aggressive phenotypes. Overall, TP53 (65%), ERBB2 (27%), and GATA3 (17%) showed statistically significant higher alteration frequencies in West Africans and African Americans. In contrast, PIK3CA (24%) was less frequently mutated. Of note, GATA3 mutation was statistically significantly more frequent in Nigerians (39%) and African Americans (16.7%) compared to Caucasians (10.5%), in ER-positive cancers. Analysis on Structural Variants (SV), on the other hand, has shown that the genome-wide SV counts among three populations are comparable in ER-negative cancers, while Nigerians have significantly more SV counts compared to African Americans (P=0.0013) or European Americans (P=2.9x10-5) in ER-positive cancers. Similarly, genome-wide substitution patterns in ER+ and ER- cancers varied widely by race/ethnicity. In ER- cases, West Africans carried the highest proportion of canonical APOBEC-associated substitutions, particularly C>T transitions. Conversely, European Americans with ER+ disease showed a higher proportion of C>T than both West Africans (Welch t-test P = 0.044) and African Americans (Welch t-test P = 0.011). Mutation signature analyses highlighted multiple APOBEC signatures, with notable contribution differences across ancestry and ER status. A signature likely corresponding to DNA damage repair correlated with the proportion of genetic ancestry, being most prevalent in European Americans and least common in Nigerians, particularly in ER-negative cancers, with African Americans showing a degree of this signature's contribution in between the two populations (linear model adjusted for age, P=1.0x10-10). Conclusions: Overall, our data suggests mutation spectra differences in across race/ethnicity and geography. Identification of molecular characteristics such as higher rates of HER2 enriched tumors and higher rates of GATA3 mutations in ER positive tumors are beginning to reveal the genomic basis of race-associated phenotypes and outcomes in breast cancer. Population differences in frequency and spectrum of mutations should now inform the design of innovative clinical trials that improve health equity and accelerate Precision Oncology care in diverse populations. Citation Format: Olopade OI, Pitt JJ, Riester M, Odetunde A, Yoshimatsu T, Labrot E, Ademola A, Sanni A, Okedere B, Mahan S, Nwosu I, Leary R, Ajani M, Johnson RS, Sveen E, Zheng Y, Wang S, Fitzgerald DJ, Grundstad J, Tuteja J, Clayton W, Khramtsova G, Oludara M, Omodele F, Benson O, Adeoye A, Morhason-Bello O, Ogundiran T, Babalola C, Popoola A, Morrissey M, Chen L, Huo D, Falusi A, Winckler W, Obafunwa J, Papoutsakis D, Ojengbede O, White KP, Ibrahim N, Oluwasola O, Barretina J. Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD8-05.
Background: African American breast cancer patients have worse survival rates than European American patients. Although racial differences in the distribution of breast cancer intrinsic subtype are known, it is unclear if there are other inherent genomic differences contributing to this racial outcome disparity. Methods: We defined patient race based on genomic ancestry and compared multiple molecular features of breast cancer between 154 black and 776 white patients in The Cancer Genome Atlas (TCGA). We examined the contribution of these molecular features to survival outcomes using Cox proportional hazards models. We also estimated the heritability of breast cancer subtypes using a mixed effect model. Results: Compared to whites, black patients had higher odds of basal-like (odds ratio=3.80, p<0.001) and HER2-enriched (odds ratio=2.22, p=0.027) breast cancers in reference to luminal A subtype. Beyond differences in relative frequency of intrinsic subtypes, black and white patients had distinct gene expression, protein expression, and somatic mutation landscapes. However, the majority of these molecular differences were eliminated after adjusting for subtype; in the subtype-adjusted models, we found 142 genes, 16 methylation probes, 4 copy number segments, 1 protein, and no somatic mutation were differentially expressed or present between black and white patients. Using the top 40 differentially expressed genes, we built a race-enriched gene signature, which had excellent capacity of distinguishing breast tumors from black versus white patients (c-index=0.852 in the validation dataset). We also estimated the heritability of breast cancer subtype (basal vs. non-basal) to be 0.436 (p=1.5x10-14) and showed that two genetic variants (rs1078806 in FGFR2, rs34084277 in BABAM1) were associated with intrinsic subtype and can partially explain racial differences in subtype frequencies. Conclusion: On the molecular level, once intrinsic subtype frequency differences are accounted for, there are few genomic or proteomic differences observed between blacks and whites. More than 40% of breast cancer subtype frequency differences may be due to genetic ancestry. These results suggest that future studies are warranted to investigate genetic and non-genetic factors that contribute to the development and progression of breast cancer subtypes in order to reduce racial disparity. Citation Format: Huo D, Hu H, Rhie SK, Gamazon ER, Cherniack AD, Liu J, Yoshimatsu TF, Pitt JJ, Hoadley KA, Troester M, Ru Y, Lichtenberg T, Sturtz LA, Shelley CS, Mills GB, Laird PW, Shriver CD, Perou CM, Olopade OI. Comprehensive comparison of breast cancer molecular portraits by African and European ancestry in the cancer genome atlas [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-11.
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