Abstract A031: Population-specific WNT pathway and MYC dysregulation in early-onset colorectal cancer

Abstract Introduction: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths and the third most commonly diagnosed cancer worldwide. While incidence and mortality have declined in high-income countries due to advances in prevention and early detection, early-onset CRC (EOCRC)—defined as diagnosis before age 50—has been rising steadily since the 1990s. This trend is particularly concerning among Hispanic/Latino (H/L), Native American, and African American populations, who have experienced some of the highest increases in EOCRC incidence. However, most molecular studies to date have focused on Non-Hispanic White (NHW) populations, leaving a significant knowledge gap regarding the genomic drivers of EOCRC in H/L patients. To address this, we investigated alterations in the WNT signaling pathway and the MYC gene, two key regulators of CRC development and progression. Methods: We performed a multi-omic analysis of CRC tumor samples from 378 Hispanic/Latino and 279 Non-Hispanic White patients in the Los Angeles area using City of Hope’s Poseidon dataset. In alignment with recommendations from the National Academies of Sciences, Engineering, and Medicine (NASEM), we applied appropriate population descriptors in our genomic analyses. Whole-exome sequencing (WES) was used to identify somatic mutations, somatic copy number alterations (SCNAs), and to estimate global ancestry. RNA sequencing was conducted to evaluate differential gene expression, pathway activity, and gene fusion events. Results: Preliminary findings indicate population-specific genomic and transcriptomic differences between H/L and NHW EOCRC patients. Emerging trends suggest variations in the WNT signaling pathway and MYC-associated gene regulation. Ongoing analyses continue to investigate mutational profiles, expression patterns, and pathway-level differences that may inform population-tailored precision oncology approaches. Additionally, we are conducting subgroup analyses comparing early-onset (EOCRC) and late-onset colorectal cancer (LOCRC) cases within the H/L cohort. Conclusion: This study presents the most comprehensive molecular characterization to date of EOCRC in Hispanic/Latino patients compared to Non-Hispanic White patients in Southern California. Our findings reveal population-specific molecular signatures that may inform future precision medicine strategies. These results underscore the value of multi-omic approaches and highlight the critical need to expand representation of historically understudied populations in cancer research to improve care quality and clinical outcomes across groups. Citation Format: Francisco G. Carranza, Brigette Waldrup, Sophia Manjarrez, Enrique I. Velazquez-Villarreal. Population-specific WNT pathway and MYC dysregulation in early-onset colorectal cancer [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 A031.