Abstract C024: Somatic Mutations in Early-Onset Colorectal Cancer: Insights from a U.S. Hispanic Cohort

The alarming rising incidence of colorectal cancer (CRC) among individuals younger than 50 years (early-onset CRC) underscores the need to identify the genetic drivers to improve personalized clinical management and outcomes. The objective of this study was to characterize the somatic mutation profile of early-onset tumors from Hispanics living in Puerto Rico (HPR), a U.S. Hispanic subpopulation with a high CRC burden. Whole exome sequencing was performed using the HiSeq4000 System (Illumina) on colorectal adenocarcinoma and corresponding mucosa samples from 62 individuals with non-familial, sporadic early-onset CRC and 25 diagnosed with average-onset CRC ( >60 years old). Somatic variant calling and annotation/visualization were performed with Strelka and Ingenuity Variant Analysis software, respectively. Mutational frequency in APC, TP53, KRAS, and SMAD4 was compared to data in TCGA and AACR Project GENIE. The mutational burden in early-onset CRC tumors from HPR was comparable to average-onset tumors. However, mutations in APC (p = 0.015), PIK3CA (p = 0.03), TP53BP1 (p = 0.03), and MUC16 (p = 0.02) were more common in average-onset tumors. The aflatoxin exposure signature (SBS24) was only identified in early-onset tumors, with 22.4% showing a signature fraction >10%. When compared to data on tumors in the TCGA and GENIE datasets, early-onset CRC tumors from HPR showed a distinct somatic mutational frequency in key driver genes. Early-onset CRC tumors display distinct somatic mutational profile compared to average-onset tumors. Additional studies with larger, diverse samples are crucial for understanding the population-specific underlying mechanisms leading to early-onset disease. Maria Gonzalez-Pons, Julie Dutil, Ingrid Montes-Rodríguez Montes-Rodríguez, Luis D. Borrero-Garcia, Lenis Rovira-Torres, Leslie Casiano, Anna M. Napoles, Jung S. Byun, Eliseo Perez-Stable, Kevin L. Gardner, Marcia Cruz-Correa. Somatic mutations in early-onset colorectal cancer: insights from a U.S. Hispanic cohort [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C024.