Abstract C010: Genes with African ancestry-specific expression in TNBC tumors also show population-specific baseline differences in normal mammary tissue
Authors: Martini Rachel , Robine Nicolas , Kyei Ishmael , Adjei Ernest , Bekele Mahteme , Elemento Olivier , Newman Lisa , Davis Melissa 
Published: January 2023

Abstract
Our recent efforts to define ancestry-specific drivers in triple negative breast tumors (TNBC) has been sharply focused on identifying African (AFR) ancestry-associated gene signatures, which we have reported to be distinct from traditional approaches using SRR to categorize patients. In our AFR ancestry enriched TNBC cohort, we have identified a 613 gene signature associated with AFR ancestry, which is enriched in previously implicated canonical pathways, such as RNA post-transcriptional modification and chronic inflammation. We also reported a significant enrichment in disease/function terms associated with immune cell trafficking, where increasing African ancestry was associated with predicted activation of immune cell migration, and inhibition of immune cell activation. While these associations were determined in the TNBC tumor environment, involvement of this 613 AFR ancestry-associated gene signature has yet to be explored in the context of non-diseased breast/mammary tissue. At present, we obtained gene expression (TPM) and ancestry data from the GTEx cohort. Of 459 patients with gene expression data available for breast/mammary tissue, 47 of those were found to be of African ancestry, and 20 identified as female, and were used in subsequent analyses. We found that 17 of the 613 AFR ancestry-associated genes from TNBC tumors were also associated with AFR ancestry in non-diseased breast/mammary tissue. Interestingly we observed that some genes had differencing directionality/correlation between non-diseased and tumor tissue. Of the 17 genes, 7 were positively associated with AFR ancestry in both cohorts, including: AGMAT, CYBA, HEATR3, KCNAB2, PTGES, RAB42, and SHPK. Eight genes were found to be positively associated with AFR in normal, but negatively associated in TNBC (AC068279.3, AP001434.2, C12orf60, FNDC3B, HNRNPA1P50, RP11-214O14.1, SNORA53 and SPATA20P1). The remaining 2 were negatively associated with AFR in normal, and positively associated in tumor (AVPR2 and FAM26D). Tumor agnostic survival analysis using TCGA BRCA cohort data shows some race-specific differences in overall survival of these genes. Specifically, higher expression of AVPR2 and CYBA, and lower expression of AGMAT and SNORA53 show benefit among AA patients, but not EA patients (ns). Pathway analysis of the 17 genes shows significant enrichment with growth of mammary tumor (p = 7.3 E-07) and inflammatory response (p = 2.5 E-07) disease and function terms, specifically related to predicted activation of IFNG, AKT1, and FOS. Ancestry-specific differences in gene expression that are present in non-malignant tissue may implicate baseline differences that could play a significant role in later tumor etiology. Interestingly, 10 of 17 genes showed differing association with African ancestry, potentially revealing malignancy-induced changes to these pathways. Further analyses and curation of robust and diverse datasets of non-diseased tissue is needed to fully contextualize these findings.
Citation Format: Rachel Martini, Nicolas Robine, Ishmael Kyei, Ernest Adjei, Mahteme Bekele, Olivier Elemento, Lisa Newman, Melissa Davis. Genes with African ancestry-specific expression in TNBC tumors also show population-specific baseline differences in normal mammary tissue [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C010.