Breast Cancer-Protective Genetic Variant Common in Women of Indigenous American Genetic Ancestry Is a cis-eQTL for RMND1, ARMT1, and CCDC170 in HER2-Enriched Tumor Subtypes.

Breast cancer genome-wide association studies in Hispanic/Latina women in the United States and Latin America have identified independent risk variants in the 6q25 region, including the protective variant rs140068132, located upstream of the estrogen receptor 1 (ESR1) gene. The molecular mechanisms linking this and other variants to breast cancer risk remain poorly understood. To investigate the potential functional role of rs140068132, we analyzed the association between this variant and gene expression in breast cancer tissue. We performed RNA sequencing on 270 tumors from the Peruvian Genomics of Breast Cancer Study and determined intrinsic tumor subtypes using PAM50. The effect of rs140068132 on gene expression across tumor subtypes was assessed using models adjusted for age at diagnosis, Indigenous American genetic ancestry, PAM50 subtype, and an interaction term between tumor subtype and SNP genotype. Subtype-specific effects of the protective rs140068132-G allele were observed in HER2-enriched tumors, with increased expression of ARMT1, RMND1, and CCDC170. These results suggest that in breast cancer tissue from Peruvian patients, rs140068132 influences the expression of multiple genes in a subtype-specific manner, likely acting through a regulatory element at 6q25 that modulates gene expression in cis depending on cellular context. SIGNIFICANCE: A protective germline variant, common in women of Indigenous American ancestry, upregulates the expression of cis-genes only in HER2-enriched tumors, providing valuable information for model selection in downstream mechanistic studies.