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 American than Caucasians (33.3% vs 14.9%). Although, more African American 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 American 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 American vs 27% in Caucasians; PIK3CA: 23% in African American vs 34% in Caucasians; and MLL3: 12% in African American 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 common established tumor regulatory pathway genes. Other modifiable factors may exist that contribute to the racial disparity in TNBC.

Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers

“…These pan-cancer findings are consistent with previous results from studies based on a single cancer type. For example, recent studies on breast cancer from the TCGA cohort (Ademuyiwa et al, 2017; Huo et al, 2017; Keenan et al, 2015) demonstrated that AAs had more TP53 mutations and fewer PIK3CA mutations. These observations not only further our understanding of the contributions of genetic ancestry to cancer disparities, but may also inform personalized treatment of cancer patients from racial/ethnic minority groups.…”

“…This shared genetic background may confer similarities in cancer incidence and outcomes in populations. Recent large-scale genomic profile studies in individual cancer types, such as prostate (Huang et al, 2017; Petrovics et al, 2015; Powell et al, 2013; Wang et al, 2017), breast (Ademuyiwa et al, 2017; Huo et al, 2017; Keenan et al, 2015; Loo et al, 2011), colon (Guda et al, 2015), lung (Araujo et al, 2015; Campbell et al, 2017; Kytola et al, 2017), gastric (Schumacher et al, 2017), esophageal (Deng et al, 2017), and kidney (Krishnan et al, 2016) cancers have robustly demonstrated that genomic differences in cancers exist among distinct racial and ethnic populations. Consistently, it has been reported that the genetic background of patients may influence specific somatic alterations in cancer genomes during tumorigenesis (Carter et al, 2017).…”

Germline Mutations in Triple-Negative Breast Cancer

“…Rather than being a biological entity, TNBC is a heterogeneous disease, and subtyping is necessary to establish molecular-based therapies [7]. Different subgroups of TNBC have been identified on the basis of protein expression, mRNA signatures, and genomic alterations, either on the somatic and/or the germline level [6,8,9]. Clinical trials of targeted therapies (e.g., immune checkpoint inhibitors, androgen receptor inhibitors, poly(ADP-ribose)polymerase (PARP) inhibitors, vascular endothelial growth factor receptor inhibitors) and platinum-based therapies in TNBC are ongoing, which have recently been reviewed in detail [6,10,11].…”

Pan‐cancer clinical and molecular analysis of racial disparities

“…However, other observations suggest a role for molecular differences in cancer survival disparities. 11 Whereas some studies have explored somatic alterations in individual cancers, [12][13][14] little is known about how the macroenvironment affects the epigenetic landscape among the different races. 9 A comparison of TNBC in AA versus EA patients has demonstrated a gene expression signature consistent with increased loss of BRCA1 expression, increased activation of insulin-like growth factor 1 receptor, and increased expression of vascular endothelial growth factor-activated genes in AA patients.…”

“…10 In addition, AA patients with breast, head and neck, or endometrial cancer have higher levels of chromosomal instability and frequency of TP53 mutations and CCNE1 amplification than white patients. 11 Whereas some studies have explored somatic alterations in individual cancers, [12][13][14] little is known about how the macroenvironment affects the epigenetic landscape among the different races. 15,16 Epigenetic differences are particularly relevant because they can be shaped by environmental factors, such as chronic stress, social interactions, and toxins.…”