Differences in the mutational landscape of triple-negative breast cancer in African Americans and Caucasians

Abstract

Background: Triple-negative breast cancer (TNBC) occurs at higher frequency in African Americans compared with Caucasians. It is unclear if the biology of TNBC is different in African American versus Caucasians. In this study, we sought to evaluate racial differences in the molecular pathology of TNBC.

Methods: Using data from The Cancer Genome Atlas, we identified TNBC patients with information on race. We analyzed differences in clinical characteristics, tumor somatic mutations, and gene expression patterns by race from whole exome and microarray data.

Results: 1104 patients were identified, of which 178 had TNBC. TNBC was more frequent in African Americans than Caucasians (33.3 vs 14.9%). Although more African Americans than Caucasians overall were classified as basal-like from PAM50 gene expression (34.8 vs 16.1%), no differences in the TNBC cohort were observed. Median tumor somatic mutation counts were higher in African Americans versus Caucasians (39.5 vs 34), but no racial differences in the mutation counts in TNBC were observed. Somatic mutation analysis revealed racial differences in specific high prevalence genes in all patients (TP53 46% in African Americans vs 27% in Caucasians; PIK3CA 23% in African Americans vs 34% in Caucasians; and MLL3 12% in African Americans vs 6% in Caucasians). TNBC patients did not have any specific high prevalence genes associated with racial differences. There were no racial differences in gene expression patterns in selected genes involved in breast cancer biology. Overall, African Americans had shorter TTP and worse DFS. Racial differences in clinical outcomes were not observed in TNBC.

Conclusion: The mutational landscape of TNBC is similar between African Americans and Caucasians. The higher frequency of TNBC in African Americans is therefore not associated with a different genomic profile of commonly established tumor regulatory pathway genes. Other modifiable factors may exist that contribute to the racial disparity in TNBC.

Keywords: Genomics; Survival; Triple negative breast cancer.

Figure 1. PAM50 classification by gene expression analysis

Pie chart A- Shows all patients subdivided by race, Pie chart B- TNBC patients only subdivided by race. Dark blue indicates basal-like, red is HER2 positive, green is Luminal A, purple is Luminal B, light blue is Normal.

Figure 2. Distribution of somatic mutation number per tumor for TNBC versus non-TNBC

Patients. Box and whisker plot shows the distribution of somatic mutation number per tumor for TNBC versus non-TNBC patients with interquartile range, median, and upper and lower quartiles.

Figure 3

Distribution of somatic mutation number per tumor for A- all patients and B- TNBC patients only. Box and whisker plots shows the distribution of somatic mutation number per tumor for A- all patients subdivided by race, B-TNBC patients only subdivided by race with interquartile range, median, and upper and lower quartiles.

Figure 4

Heat map representation of selected genes in TNBC only patients. Each row represents a gene and each column represents a patient. African American (A) patients located on the right hand side, while Caucasian (C) patients located on the left. Red indicates upregulation, green indicated downregulation, black indicates no change.

Figure 5

Kaplan-Meier product limit estimates of disease free survival stratified by race at 6 years follow-up. Blue survival curve indicates African American, red curve indicates Caucasian.

Figure 6

Kaplan-Meier product limit estimates of disease free survival stratified by PAM50 status and race. Blue survival curve indicates African American basal-like, red curve indicates African American non basal-like, green curve indicates Caucasian basal-like, brown curve indicates Caucasian non basal-like.