Abstract 2136: Genetic ancestry dependent variability in stromal cells: An unexplored player in breast cancer disparity

Abstract Genetic ancestry dependent variability in cancer incidence, mutation patterns, response to chemotherapy, and outcome has been documented. While an association between social determinants of health and breast cancer disparity has already been established, there is emerging evidence for genetic ancestry dependent variability in normal breast biology impacting breast cancer biology and potentially outcome. Tumor biology studies in the context of genetic ancestry and disparity have often focused on intrinsic properties of tumor cells or tumor infiltrating immune cells. However, other stromal cell types have received very little attention. Through immunohistochemistry of breast tissues from healthy women of African and European ancestry and primary cell culturing system, we had previously demonstrated enrichment of a stromal cell population called PZP cells (PROCR+/ZEB1+/PDGFRA+) with mesenchymal stem-like and fibroadipogenic properties in the normal breast tissues of women of African ancestry. In this study, we used single nuclei ATAC-seq and/or RNA-seq to further characterize stromal fibroblasts in the breast tissues of women of Ashkenazi Jewish-European, European, Indigenous American, Hispanic-European, African, and Asian ancestry. Among eight fibroblast cell clusters generated from women of African and European ancestry, only three cell clusters overlapped between two groups. While Complement Factor D (CFD, also called adipsin) expression was observed in unique fibroblast clusters of African ancestry, the expression of Insulin-like Growth Factor 1 (IGF1) was enriched in clusters unique to European ancestry. Interestingly, previous studies have demonstrated African ancestry-specific genomic variants for CFD linked to cardiometabolic disorders. Additional genes that showed genetic ancestry dependent variability in expression within fibroblasts include ABCA10, ABCA9, ABCA8, NEGR1 (enriched in African ancestry), MMP16, MAGI1, KIAA1217, PTPRK and SEMA5A (enriched in European ancestry). NEGR1 (Neuronal Growth Regulator 1) is a trans-neural growth promoting factor, whereas PTPRK (Protein Tyrosine Phosphatase Receptor Type K) is a negative regulator of EGFR signaling. These results suggest genetic ancestry dependent variability in stromal-epithelial cell communications under normal and cancerous conditions. These genetic ancestry dependent differences could impact intracellular signaling networks in epithelial cells with consequential effects on cancer incidence, mutation patterns, drug sensitivity, and outcome. Citation Format: Poornima Bhat-Nakshatri, Hongyu Gao, Cihat Erdogan, Yunlong Liu, Harikrishna Nakshatri. Genetic ancestry dependent variability in stromal cells: An unexplored player in breast cancer disparity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2136.