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.