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Original Investigation
December 2017

Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas

Author Affiliations
  • 1Department of Public Health Sciences, The University of Chicago, Chicago, Illinois
  • 2Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois
  • 3Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania
  • 4Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles
  • 5Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
  • 6Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee
  • 7The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts
  • 8Committee of Genetics, Genomics, and Systems Biology, The University of Chicago, Chicago, Illinois
  • 9Department of Genetics and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill
  • 10Department of Epidemiology, The University of North Carolina at Chapel Hill
  • 11The Research Institute, Nationwide Children’s Hospital, Columbus, Ohio
  • 12Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison
  • 13Buck Institute for Research on Aging, Novato, California
  • 14Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston
  • 15Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan
  • 16Clinical Breast Care Project, Murtha Cancer Center, Walter Reed National Military Medical Center/Uniformed Services University of the Health Sciences, Bethesda, Maryland
JAMA Oncol. 2017;3(12):1654-1662. doi:10.1001/jamaoncol.2017.0595
Key Points

Question  What are the tumor biological differences in invasive breast cancers from patients of African and European ancestry?

Findings  In the cohort study from The Cancer Genome Atlas, a racial disparity in breast cancer–free interval and distribution of aggressive subtypes of breast cancers was detected. After taking into account differences in prevalence of intrinsic subtypes, modest molecular differences in gene expression, protein expression, somatic mutations, and DNA methylation patterns were observed, and most significantly, higher genetic contribution to estrogen receptor–negative breast cancer was seen in black patients than in white patients.

Meaning  Biological differences between breast cancers in blacks and whites may be linked to differences in the distribution of germline genetic variants, and interventions to improve cancer risk assessment and optimal use of more effective targeted therapies have the potential to close the widening mortality gap between black and white patients with breast cancer.


Importance  African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities.

Objectives  To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes.

Design, Setting, and Participants  Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas.

Main Outcomes and Measures  Breast cancer–free interval, tumor molecular features, and genetic variants.

Results  Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11).

Conclusions and Relevance  On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women.