Abstract PS3-03-13: Global Ancestry Shapes Clinical and Genetic Profiles in an Admixed Colombian Breast Cancer Cohort

Abstract Background: Breast cancer (BC) susceptibility is driven by a complex interplay of modifiable and non-modifiable risk factors. While the impact of BRCA1 and BRCA2 pathogenic/likely pathogenic variants (PVs) is well documented, the contribution of genetic ancestry to the distribution of PVs in BRCA1/2 and other homologous recombination repair (HRR) genes remains understudied in genetically admixed populations such as Colombians. Methods: Whole-exome sequencing data from 358 unselected Colombian women with BC were analyzed for genetic ancestry. Among them, 24 individuals were identified as carriers of PVs in BRCA1 (n=3), BRCA2 (n=10), PALB2 (n=2), ATM (n=5), CHEK2 (n=2), BARD1 (n=1), and RAD51D (n=1), as classified by ACMG/AMP criteria. Raw BAM files underwent preprocessing, quality control, and joint genotyping, yielding 14.9 million variants. Quality filtering using PLINK v1.9 included genotype call rate (<90%), Hardy-Weinberg equilibrium (p > 1e-6), minor allele frequency (>0.1), and linkage disequilibrium pruning. Samples with >25% missingness were excluded, resulting in a final dataset of 344 individuals and 95,671 variants (genotyping rate: 99.93%). Global ancestry proportions were estimated using principal component analysis with reference populations from the 1000 Genomes and Human Genome Diversity Projects, specifically African (AFR), European (EUR), and Native American (NAM) populations. Statistical comparisons of ancestry proportions were performed across clinical variables (e.g., age at diagnosis, family history), genetic status (PVs carriers vs non-carriers), and tumor subtypes. Results: Global ancestry was predominantly EUR (mean ∼53%), followed by NAM (∼36%) and AFR (∼10%). Significant differences in ancestry distribution were observed across clinical subgroups. AFR ancestry was higher among cases born in the Caribbean and Pacific coast regions (18% and 11%, respectively; p < 0.001), while EUR ancestry was higher among those from the Andean and Plains regions (54% and 60%, respectively; p < 0.001). The NAM component was more homogeneous across regions (34-38%). Higher EUR ancestry was associated with lower rates of breastfeeding and higher reported oral contraceptive use (p < 0.05 for both). EUR ancestry was higher in individuals with ER-positive tumors compared to ER-negative tumors (54% vs. 51%, respectively, p < 0.05), whereas AFR ancestry was higher in ER-negative (8% vs. 6% in ER-positive, p < 0.05) and PR-negative tumors (8% vs. 5% in PR-positive, p < 0.05). A higher EUR component was observed among those with a positive family history (55%) (p = 0.057) and PVs carriers in BC-related genes (58%). Two cases with CHEK2PVs [c.349A>G and c.1100delC] had 71% EUR ancestry, significantly higher than non-carriers (54%, p < 0.05), consistent with their Northern/Central European founder origins. Among the 24 PV carriers, luminal subtypes predominated (63%), particularly in ATM (100%) and BRCA2 (80%) carriers. Four of five ATM PV carriers with ancestry estimates showed predominantly EUR ancestry (49-59%). The ATM splice-site variant c.5496+2_5496+5delTAAG was identified in three unrelated individuals from the Andean region—two of whom have predominantly European ancestry and one with missing ancestry data. Conclusions: Our findings demonstrate significant associations between global ancestry proportions and key clinical and genetic features in an admixed Colombian BC cohort. To further elucidate the genetic and demographic factors influencing the frequency, distribution, origin, and potential impact of PVs identified in this cohort, we have initiated ongoing local ancestry estimations and haplotype analyses. This study highlights the importance of ancestry-informed analyses to improve risk stratification and guide precision medicine approaches in admixed populations. Citation Format: W. A. Mantilla, Y. T. Zambrano-O, L. Rey-Vargas, D. C. Sierra-Diaz, M. Lema, D. Y. Fonseca-Mendoza, S. J. Serrano-Gomez, C. M. Restrepo, M. C. Sanabria-Salas. Global Ancestry Shapes Clinical and Genetic Profiles in an Admixed Colombian Breast Cancer Cohort [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-13.