Zavala, Valentina A, Casavilca-Zambrano, Sandro, Navarro-Vásquez, Jeannie, Castañeda, Carlos A, Valencia, Guillermo, Morante, Zaida, Calderón, Monica, Abugattas, Julio E, Gómez, Henry, Fuentes, Hugo A, Liendo-Picoaga, Ruddy, Cotrina, Jose M, Monge, Claudia, Neciosup, Silvia P, Huntsman, Scott, Hu, Donglei, Sánchez, Sixto E, Williams, Michelle A, Núñez-Marrero, Angel, Godoy, Lenin, Hechmer, Aaron, Olshen, Adam B, Dutil, Julie, Ziv, Elad, Zabaleta, Jovanny, Gelaye, Bizu, Vásquez, Jule, Gálvez-Nino, Marco, Enriquez-Vera, Daniel, Vidaurre, Tatiana, and Fejerman, Laura
BackgroundBreast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with 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 H/Ls of high Indigenous American ancestry.MethodsGenotypes 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.ResultsWe replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47-0.59], as well as the lower odds of developing hormone receptor negative (HR-) versus HR+ disease (OR, 0.77; 95% CI, 0.61-0.97). Models, including 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 with HR+HER2-. Inclusion of other risk-associated variants did not change these observations.ConclusionsThe 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.ImpactThese 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.