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. Array-based genotyping and ADMIXTURE analysis were used for genetic ancestry evaluation. Breast cancer subtypes were defined by IHC and the gene expression-based PAM50 algorithm. The distribution of genetic ancestry, including European, 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 European ancestry was significantly associated with a 14% decrease in the odds of developing HER2-enriched 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 with a 21% increase in the probability of having HER2-enriched 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 affected by the size and heterogeneity of the Molecular Profile Breast Cancer Study cohort. Our research confirms previous findings of a high prevalence of HER2-dependent breast tumors among Hispanic/Latina women and strengthens 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.

Significance: The evidence in this work supports the idea that factors linked to genetic ancestry influence the prevalence of breast cancer subtypes in Latin America, potentially affecting treatment needs in the region.

Figure 1

Population structure of the 951 patients with breast cancer of the LACRN-MPBCS cohort included in this study. A, ADMIXTURE ancestry estimations obtained assuming four ancestral components for each country of origin (B) Principal component analysis (PCA) of data from all LACRN-MPBCS patients (triangles) and 158 reference subjects (dots). The two principal components of variation are shown as PC1 and PC2. C and D, Boxplots showing the distribution of each ancestry component for the whole cohort and by country, respectively. Median ancestry and IQRs are depicted; whiskers extend up to 1.5 IQR. Values outside the inter-quartile range are shown as solid dots. AFR, African; EAS, East Asian; EUR, European; IA, Indigenous American.

Figure 2

Distribution of PAM50 breast cancer subtypes according to the four most prevalent ancestral components in Latin America: European (EUR), Indigenous American (IA), African (AFR), and East Asian (EAS). Bars shown correspond to post hoc Dunn test pairwise comparisons <0.05. HER2E, HER2-enriched; LumA, luminal A; LumB, luminal B.