Genetic ancestry-dependent differences in breast cancer-induced field defects in the tumor-adjacent normal breast.

Purpose: Genetic ancestry influences evolutionary pathways of cancers. However, whether ancestry influences cancer-induced field defects is unknown. The goal of this study was to utilize ancestry-mapped true normal breast tissues as controls to identify cancer-induced field defects in normal tissue adjacent to breast tumors (NATs) in women of African American (AA) and European (EA) ancestry. Experimental Design: A tissue microarray comprising breast tissues of ancestry-mapped 100 age-matched healthy women from the Komen Tissue Bank (KTB) at Indiana University (Indianapolis, IN) and tumor-NAT pairs from 100 women (300 samples total) was analyzed for the levels of ZEB1, an oncogenic transcription factor that is central to cell fate, mature luminal cell-enriched estrogen receptor alpha (ER alpha), GATA3, FOXA1, and for immune cell composition. Results: ZEB1(+) cells, which were localized surrounding the ductal structures of the normal breast, were enriched in the KTB-normal of AA compared with KTB-normal of EA women. In contrast, in EA women, both NATs and tumors compared with KTB-normal contained higher levels of ZEB1(+) cells. FOXA1 levels were lower in NATs compared with KTB-normal in AA but not in EA women. We also noted variations in the levels of GATA3, CD8(+) T cells, PD1(+) immune cells, and PDL1(+) cell but not CD68(+) macrophages in NATs of AA and EA women. ER alpha levels did not change in any of our analyses, pointing to the specificity of ancestry-dependent variations. Conclusions: Genetic ancestry-mapped tissues from healthy individuals are required for proper assessment and development of cancer-induced field defects as early cancer detection markers. This finding is significant in light of recent discoveries of influence of genetic ancestry on both normal biology and tumor evolution.