Abstract 5066: Association between genetic ancestry and somatic mutational profiles in colorectal cancer

Abstract Colorectal cancer (CRC) mortality rates differ across populations and differences are not fully accounted for by sociodemographic factors and access to care. Opportunities exist to better understand biological determinants of disparities by expanding cancer genomic datasets to include profiles of tumors from patients from varied communities. Using whole-exome sequencing data from the Latino Colorectal Cancer Consortium (LC3) and additional datasets, we characterized somatic mutational profiles by ethnicity and genetically-inferred ancestry. We hypothesized that ancestral haplotypes that vary across populations contribute to differential somatic mutational profiles. Somatic mutations were called from paired tumor and germline/normal samples using an analysis pipeline including Burrows-Wheeler MEM Aligner, the Genome Analysis Toolkit (GATK), MuTect, Strelka, MuSE, SomaticSniper, freebayes, and Lancet. Inherited variants were identified using GATK. Global proportions of African, East Asian, European, Native American, and South Asian ancestries were estimated using ADMIXTURE based on the 1000 Genomes Project and the Human Genome Diversity Project. Among the 1,243 primary CRC cases included, 391 (31.5%) were Latino, 488 (39.3%) were non-Latino. Associations between global ancestry and somatic mutational features were examined using logistic regression. Among commonly mutated genes in CRC, tumors from Latino participants exhibited lower frequencies of mutations in BRAF (OR=0.59, 95%CI=0.34-0.99, p=0.048), CTNBB1 (OR=0.54, 95%CI=0.30-0.96, p=0.037), FBXW7 (OR=0.61, 95%CI=0.38-0.99, p=0.045), KRAS (OR=0.71, 95%CI=0.52-0.95, p=0.023), but higher frequency of mutations in CDC27 (OR=11.74, 95%CI=1.39-99.09, p=0.024) and SMAD2 (OR=2.30, 95%CI=1.08-4.89, p=0.03) compared to non-Latino patients. In addition, African ancestry was significantly associated with higher odds of mutations in APC (OR=1.10, 95%CI=1.02-1.18, p=0.013) and PIK3CA (OR=1.08, 95%CI=1.00-1.15, p=0.037), while Native American ancestry was associated with lower odds of mutations in BRAF (OR=0.83, 95%CI=0.70-0.97, p=0.02) and FBXW7 (OR=0.85, 95%CI=0.75-0.97, p=0.012). Genome-wide analyses revealed that global genetic ancestry was associated with mutation status in CFAP54, LMBRD2, MUC12, and TTC6 (FDR-adjusted 4-df LRT p<0.05). Native American ancestry was associated with reduced odds of mutations in LMBRD2 (OR= 0.47, 95%CI=0.24-0.95, p=0.034), but with higher odds of mutations in CFAP54 (OR=1.32, 95%CI=1.17-1.49, p=7.55x10-06), MUC12 (OR=1.29, 95%CI=1.08-1.55, p=0.0049), and TTC6 (OR=1.31, 95%CI=1.11-1.53, p=0.0011). Tumor mutation burden was significantly reduced in Latino patients compared to non-Latino patients (OR= 0.78, 95%CI=0.64-0.94, p=0.012). These findings advance precision medicine efforts by improving our understanding of ancestry-associated molecular heterogeneity. Citation Format: Marco Matejcic, Jamie Teer, Daniel Sobieski, Eric M. Cockman, Esther Jean-Baptiste, Nathalie Nguyen, Diana B. Diaz, Ya-Yu Tsai, Hannah J. Hoehn, Kritika Shankar, Rusché Wilson, Karina Brito, Allyson Koepfler, Seth Felder, Julian Sanchez, Nicole Catalina Lorona, W. Douglas Cress, Teresita Muñoz-Antonia, Idhaliz Flores, Edna Gordian, Jose Oliveras Torres, Ozlen Saglam, Kun Jiang, Clifton Fulmer, Domenico Coppola, Erin M. Siegel, Mariana C. Stern, Jane C. Figueiredo, Stephanie L. Schmit. Association between genetic ancestry and somatic mutational profiles in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5066.