Abstract
Breast cancer largely dominates the global cancer burden statistics; however, there are striking disparities in mortality rates across countries. While socioeconomic factors contribute to population-based differences in mortality, they do not fully explain disparity among women of African ancestry (AA) and Arab ancestry (ArA) compared to women of European ancestry (EA). In this study, we sought to identify molecular differences that could provide insight into the biology of ancestry-associated disparities in clinical outcomes. We applied a unique approach that combines the use of curated survival data from The Cancer Genome Atlas (TCGA) Pan-Cancer clinical data resource, improved single-nucleotide polymorphism-based inferred ancestry assignment, and a novel breast cancer subtype classification to interrogate the TCGA and a local Arab breast cancer dataset. We observed an enrichment of BasalMyo tumors in AA patients (38 vs 16.5% in EA, p = 1.30E − 10), associated with a significant worse overall (hazard ratio (HR) = 2.39, p = 0.02) and disease-specific survival (HR = 2.57, p = 0.03). Gene set enrichment analysis of BasalMyo AA and EA samples revealed differences in the abundance of T-regulatory and T-helper type 2 cells, and enrichment of cancer-related pathways with prognostic implications (AA: PI3K-Akt-mTOR and ErbB signaling; EA: EGF, estrogen-dependent and DNA repair signaling). Strikingly, AMPK signaling was associated with opposing prognostic connotation (AA: 10-year HR = 2.79, EA: 10-year HR = 0.34). Analysis of ArA patients suggests enrichment of BasalMyo tumors with a trend for differential enrichment of T-regulatory cells and AMPK signaling. Together, our findings suggest that the disparity in the clinical outcome of AA breast cancer patients is likely related to differences in cancer-related and microenvironmental features.
Highlights
As we enter an era of personalized medicine in oncology, largescale studies have been instrumental in deciphering the pathogenesis and evolution of tumors
Ancestries were assigned using principal component (PC) analysis of single-nucleotide polymorphisms (SNPs) array genotyping calls following the method as described by CarrotZhang et al.[48] (Supplementary Fig. 1)
An increasing effort is expended to decipher the molecular differences that are associated with global disparities in breast cancer outcomes
Summary
As we enter an era of personalized medicine in oncology, largescale studies have been instrumental in deciphering the pathogenesis and evolution of tumors. Public data repositories such as The Cancer Genome Atlas (TCGA) have enabled researchers to define the genomic landscape of different types of cancers, including breast cancer. African-American women with early-stage TNBCs have been shown to exhibit a lower pathological complete response to neoadjuvant chemotherapy[17]. This discrepancy in clinical outcome remains after correcting for socioeconomic factors, suggesting the presence of molecular differences by ancestry[18,19].
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