TROP2 and immune gene expression by African ancestry in triple-negative breast cancer

Abstract

Purpose: TROP2 is a treatment target in triple-negative breast cancer (TNBC). TACSTD2 encodes TROP2, while PDCD1 encodes the immune protein PD-1. We investigated whether these genes differ by race or African genetic ancestry and whether the reported link between higher TACSTD2 and lower immune-gene expression partly reflects the mixture of cells in tumor samples. Methods: We analyzed TNBC tumors from TCGA (n = 107) and GSE268851 (n = 253; ancestry data for 229), together with spatial, normal-breast, and protein datasets. Regression models adjusted for age, tumor stage, and a score based on epithelial gene expression. We compared TACSTD2 with other epithelial markers using paired bootstrap analysis. Results: TACSTD2 was detected in nearly all tumors, with no significant differences by race or ancestry. Higher African ancestry was linked to higher PDCD1 expression in TCGA (P = 0.00039), but not in GSE268851. In GSE268851, higher TACSTD2 remained associated with lower CD8A, GZMB, and cytotoxic score after epithelial adjustment (all q < 0.003). These associations were stronger than those for EPCAM; the CD8A association was also stronger than that for KRT8. TACSTD2 was 1.55-fold higher in TNBC than in normal breast and correlated with TROP2 protein (Spearman rho = 0.74). Conclusion: TACSTD2 was widely expressed in the TNBC groups studied, while the ancestry-PDCD1 association differed between cohorts. Epithelial gene expression did not fully explain some negative TACSTD2-immune associations, and some were stronger than those for other epithelial markers such as EPCAM.