Genetic ancestry, Intrinsic Tumor Subtypes, and Breast Cancer Survival in Latin American Women.

Abstract

This study investigates the relationship between genetic ancestry, breast cancer subtypes, and survival outcomes among 951 locally advanced breast cancer cases from Argentina, Brazil, Chile, Mexico, and Uruguay, participating in the Molecular Profile of Breast Cancer Study (MPBCS). Array-based genotyping and ADMIXTURE analysis was used for genetic ancestry evaluation. Breast cancer subtypes were defined by immunohistochemistry and the gene expression-based PAM50 algorithm. The distribution of genetic ancestry, including European (EUR), Indigenous American (IA), African (AFR), and East Asian components, revealed a heterogeneous genetic admixture across countries, with the highest IA ancestry observed in Chile (30.9%) and Mexico (30.8%). Testing the relationship between genetic ancestry and breast cancer subtypes demonstrated that a 10% increase in EUR ancestry was significantly associated with a 14% decrease in the odds of developing HER2-enriched (HER2E) breast cancer, after adjustment by age, nodal status, and the AFR component (adj.p= 0.021, Luminal A as reference). Accordingly, a 10% increase in IA ancestry was associated to a 21% increase in the probability of having HER2E breast cancer (adj.p=0.022). IA ancestry also significantly increased overall survival after adjustment by age, nodal status, and AFR ancestry, although this result is controversial and may be impacted by the size and heterogeneity of the MPBCS cohort. Our research confirms previous findings of a high prevalence of HER2-dependent breast tumors among Hispanic/Latina women and strengthen the hypotheses of the existence of either population-specific genetic variant(s) or of other ancestry-correlated factors that impact HER2 expression in breast cancer consistently across different Latin American regions.