Background:

Breast cancer incidence in the United States is lower in Hispanic/Latina compared to African American/Black or Non-Hispanic White women. An Indigenous American breast cancer protective germline variant (rs140068132) has been reported near the Estrogen Receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in Hispanic/Latinas of high Indigenous American ancestry.

Methods:

Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses including other risk-associated polymorphisms in the region.

Results:

We replicated the reported association between rs140068132 and breast cancer risk overall (odds ratio (OR)=0.53, 95%CI=0.47-0.59), as well as the lower odds of developing hormone receptor negative (HR-) vs. HR+ disease (OR=0.77, 95%CI=0.61-0.97). Models including Human Epidermal Growth Factor Receptor 2 (HER2) showed further heterogeneity with reduced odds for HR+HER2+ (OR=0.68, 95%CI=0.51-0.92), HR-HER2+ (OR=0.63, 95%CI 0.44-0.90) and HR-HER2- (OR=0.77, 95%CI=0.56-1.05) compared to HR+HER2-. Inclusion of other risk-associated variants did not change these observations.

Conclusion:

The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR- and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region.

Impact:

These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies.