Differential expression between African-ancestry and White patients diagnosed with Triple-Negative Breast Cancer: EGFR, Myc, Bcl2 and β-Catenin as ancestry-associated markers

Abstract

AbstractPurposeTriple-negative breast cancer (TNBC) has a higher incidence, a younger age of onset, and a more aggressive behavior in African-ancestry women. Biological disparities have been suggested as an important factor influencing the ancestry-associated TNBC discrepancy. In this study, we sought to identify ancestry-associated differential gene and protein expression between African-ancestry and White TNBC patients, controlling for patients’ menopause status and pathological staging at diagnosis.MethodsDifferential gene expression analyses (DGEA) were performed using RNA-sequencing data from The Cancer Genome Atlas (TCGA). Gene set enrichment analysis (GSEA) and Ingenuity Pathway Analysis (IPA), with focus on network design, were performed to highlight candidate genes for further validation through immunohistochemistry of TNBC samples from patients followed in Portugal.ResultsWith 52 African-American and 90 White TNBC patients included, TCGA’s data corroborate that African-American patients have a higher TNBC incidence (28.42% vs 11.89%, p<0.0001). Particularly, premenopausal and stage II disease African-American patients also have significantly lower survival probability, comparing with White patients (log-rank p=0.019 and 0.0038, respectively). DGEA results suggest that expression profile differences are more associated with TNBC staging than with patient’s menopause status. Hippo pathway and cellular community gene sets are downregulated, while breast cancer gene set is upregulated in African-Americans, comparing with White TNBC patients. Furthermore, MAPK pathway gene set is upregulated when controlling for stage II disease. Due to their central role in highly scored networks resulted from IPA’s network design, EGFR, Myc and Bcl2 genes were selected for further validation through immunohistochemistry. We also included β-Catenin in the validation study as it is consensually reported to be required in TNBC tumorigenesis. Although patients used in the DGEA and in the immunohistochemistry experiments are geographically and culturally distinct, both groups of African-ancestry patients are mostly of western-African ancestry and, interesting, differential gene and protein expression matched.ConclusionsWe found ancestry-associated gene expression patterns between African-ancestry and White TNBCs, particularly when controlling for menopause status or staging. EGFR, Myc, Bcl2 and β-catenin gene and protein differential expression matching results in distinct populations suggest these markers as being important indicators of TNBC’s ancestry-associated development.