Abstract 5237: Regulation of genes located in 6q25 by an Indigenous American genetic variant in breast cancer patients from Peru

Genetic studies in women of Hispanic/Latina origin identified a single nucleotide polymorphism (SNP) in the 6q25 region, rs140068132, that correlates with Indigenous American (IA) ancestry and is protective against BC. The underrepresentation of Latin American populations in public databases has hindered the study of the mechanisms by which this SNP confers a protective effect. We aimed to identify IA germline variants associated with BC risk and to test their association with tumor gene expression in this region. We performed a case-control fine-mapping analysis in the 6q25 region. BC patients part of the PEGEN-BC Study (N=1809) were included as cases and women from a pregnancy outcomes study in Peru as controls (N=3334). Genome-wide genotype data were available and missing genotypes were imputed using the TOPMED Imputation Server. Logistic regression was used to test the association between each SNP and BC risk. We exome-sequenced 247 breast tumors of PEGEN-BC patients. Tumor subtype was assigned by the pam50 method. We excluded patients diagnosed with stage IV disease, with tumors classified as normal-like or as uncertain, and carriers of the GG genotype for rs140068132, leaving 242 samples. Association between rs140068132 and gene expression of genes in the 6q25 region was tested adjusting by age at diagnosis and IA ancestry. The strongest signal corresponded to rs140068132 (odds ratio (OR)=0.53, p=1.9e-21). The model adjusted by rs140068132 revealed three additional independent variants that correlate with Indigenous American ancestry: rs184135739 (OR=0.8, p=0.006), rs141057867 (OR=0.87, p=0.006) and rs140125124 (OR=1.23, p=0.015). Gene expression analysis stratified by subtype revealed that among HER2+ tumors (N=63), rs140068132 was associated with ARMT1 (fold change comparing AA to AG (FC)=1.6, p