Abstract A083: Uncovering indigenous genetic markers: eQTLs associated with HER2-positive breast cancer in Colombian women

Abstract Introduction: Important disparities in breast cancer subtypes have been observed across population groups. For instance, a higher prevalence of HER2-positive tumors has been reported among Latina women. Studies in Peruvian and Colombian women suggest that greater Indigenous ancestry is associated with an increased risk of these subtypes and with the overexpression of genes such as ERBB2, indicating a possible biological role of ancestry in these disparities. As a potential underlying biological mechanism, the presence of population-specific expression quantitative trait loci (eQTLs) has been proposed. In this context, the aim of this study was to identify Indigenous ancestry-specific eQTLs associated with the HER2-positive subtype. Methods: RNA-seq data from non-tumoral breast tissue of 183 patients from the National Cancer Institute of Colombia were analyzed to obtain genotypes using a variant-calling pipeline based on GATK4 and imputation with TOPMed, as well as normalized gene expression matrices processed with STAR and DESeq2. The identification of eQTLs was performed using the MatrixEQTL package, and local ancestry was estimated using RFMix v2.03 to ultimately filter for eQTLs enriched in Indigenous ancestry genomic regions. Results: A total of 1,605 cis- and trans-eQTLs with allele frequencies specific to the Indigenous ancestry component were identified in non-tumorous tissue. Among these, two SNPs (rs77910576 and rs114115233), located at 7p21.1, were associated in trans with increased expression of HER2 amplicon genes—ERBB2, GRB7, PGAP3, PPP1R1B, and STARD3—located at 17q12 (β=5,423.92; FDR=2.13×10-9). Additionally, a haplotype at 1p13.3, composed of rs12116550, rs12143727, rs12144827, and rs12739802, was associated with higher ERBB2 and GRB7 mRNA levels (β=1,412.88; FDR=7.07×10-4). Functional annotation revealed that rs77910576 maps to an intergenic region with affinity for the transcription factor GATA3, a key regulator of the luminal breast cancer phenotype, whereas the 1p13.3 haplotype overlaps with a region where the transcription factor E2F1 binds. Hi-C chromatin interaction data from HMEC cell lines revealed high frequencies of physical contact (observed/expected, O/E) between these eQTL regions and the HER2 amplicon loci (O/E 7p21.1–17q12 = 16.01; O/E 1p13.3–17q12 = 8.02). Analysis of clinicopathological variables by eQTL genotype revealed that the alternative alleles of rs77910576 and rs114115233 were more common among patients with HER2-positive tumors. Furthermore, a higher dosage of the alternative alleles of the 1p13.3 haplotype was associated with decreased overall and recurrence-free survival. Conclusion: These results suggest that patients with a higher proportion of Indigenous ancestry may exhibit a higher frequency of genotypes associated with increased expression of genes within the HER2 amplicon. This could contribute to a greater prevalence of HER2-positive breast cancer subtypes among Colombian patients. Citation Format: Laura Rey Vargas, Lina Maria. Bejarano, Patricia Lopez-Correa, Diego Felipe. Ballen-Lozano, Silvia Juliana. Serrano-Gomez. Uncovering indigenous genetic markers: eQTLs associated with HER2-positive breast cancer in Colombian women abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A083.