Identification of Distinct Heterogenic Subtypes and Molecular Signatures Associated with African Ancestry in Triple Negative Breast Cancer Using Quantified Genetic Ancestry Models in Admixed Race Populations

Abstract

Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n = 42) and European American (EA, n = 33) women. RNA sequencing data were analyzed to measure changes in genome-wide expression, and we utilized logistic regressions to identify ancestry-associated gene expression signatures. Using SNVs identified from our RNA sequencing data, global ancestry was estimated. We identified 156 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated in TCGA data. In AA patients, there was a higher incidence of basal-like two tumors and altered TP53, NFB1, and AKT pathways. The distinct distribution of TNBC subtypes and altered oncologic pathways show that the ethnic variations in TNBCs are driven by shared genetic ancestry. Thus, to appreciate the molecular diversity of TNBCs, tumors from patients of various ancestral origins should be evaluated.

African-Ancestry Associated Gene Expression Signatures and Pathways in Triple Negative Breast Cancer, a Comparison across Women of African Descent

“…To investigate African ancestry-specific gene expression profiles in our ICSBCS TNBC samples, we isolated our analyses to patients with significant (>35%) AFR ancestry. As previously described 26 , we performed gene-by-gene linear regression, using genetic ancestry as a continuous variable, which determined ancestry-associated gene expression. We identified gene signatures associated with AFR (n = 613) and EUR (n = 345) ancestry ( p < 0.001), with 293 genes shared between these gene signatures ( Figure 2A ) ( Supplemental Table S3 ).…”

“…After the suggested re-assignment of the IM and MSL subtypes, AAs had a predominance of UNS calls, indicating an unresolved heterogeneity that would not allow designation of a single subtype ( Figure 5A, middle ). Therefore, to ascribe a biological phenotype to these tumors, we employed a previously described median-ranking 26 which excludes the confounding influence of the immune signature genes. Our results indicate that BL1 is the predominant subtype for Ghanaians, and M is the predominant subtype for both AA and Ethiopians ( Figure 5A, bottom ).…”

Genomics and Cancer Disparities: The Justice and Power of Inclusion

“…Specifically, in the area of cancer research, new initiatives funded by the NCI and its Center for Disparities are strategically addressing cancer disparities using genomics in comparative studies to define differences across ethnic/ancestry groups. These studies are revealing novelties in tumor pathways involving metabolism, immunology, and tumor heterogeneity (10,13). These exciting new findings, in the context of cancer disparities, reveal how diversity in research can expand our general knowledge of cancer biology.…”

“…For example, the gene signatures that define breast cancer subtypes have shaped our approaches to developing research for targeted therapies; however, we also find that gene signatures have significant variation across patient groups, underlying a bias in the incidence of specific subtypes within these patient groups. Specifically, we now know that triple-negative breast cancers (TNBC) are more prevalent in non-White populations (12) and that the subtypes of TNBC, defined by the genomic signature of hundreds of genes, also show significant bias among race groups (13). Yet, knowing this does not necessarily change the course of treatment.…”

Concomitant activation of GLI1 and Notch1 contributes to racial disparity of human triple negative breast cancer progression

“…Despite higher prevalence of TNBC and poorer TNBC-related survival among AA women, very few studies have attempted to examine the molecular phenotype of AA-TNBC in direct comparison to WA-TNBC. No significant differences are reported in somatic mutations between AA-TNBC and WA-TNBC in a customized set of 151 genes ( Omilian et al, 2020 ) but elevated expression of VEGF-activated genes and proliferation-associated gene signature, altered TP53, NFB1, and AKT pathways and increased microvessel density has been associated with AA-TNBC ( Davis et al, 2020 ; Lindner et al, 2013 ). While TNBC biology that drives the aggressive progression of AA-TNBC is still imprecise, it is clear that irrespective of stage at diagnosis, AA-TNBC is more aggressive with higher metastasis and a poorer survival than WA-TNBC.…”