Abstract A039: Colorectal cancer in Hispanic and Latino populations: Genetic similarity and molecular drivers identified via multi-omics analysis

Abstract Introduction: Colorectal cancer (CRC) remains a major cause of cancer-related death and disproportionately affects Hispanic and Latino populations. To better understand the molecular underpinnings contributing to this burden, we conducted a large-scale analysis of CRC tumors, focusing on somatic mutations, transcriptional profiles, and patterns of genetic similarity—defined per NASEM guidelines as a proxy for genetic ancestry. Methods: Within the framework of the NIH/NCI Cancer Moonshot Center for Optimization of Participant Engagement for Cancer Characterization (COPECC) and PE-CGS initiative and Participant Engagement and Cancer Genome Sequencing (PE-CGS), we analyzed 131 paired tumor-normal colorectal samples from Hispanic and Latino individuals residing in the Los Angeles region. These were evaluated alongside Non-Hispanic White (NHW) tumors sourced from publicly available datasets, including AACR-GENIE. Whole-exome sequencing enabled profiling of somatic mutations, copy number alterations, and genetic similarity. RNA-seq data provided insight into gene expression changes, activated pathways, and gene fusion events. Analyses were conducted in accordance with current best practices for incorporating race, ethnicity, and ancestry-related descriptors in genomics research, as recommended by NASEM. Results: Our study identified distinctive patterns of genetic similarity in the Hispanic and Latino cohort, with a substantial subset exhibiting ancestry resembling the 1000 Genomes Project’s Peruvian-from-Lima (1KG-PEL) reference group. These ancestry patterns were associated with microsatellite stability status, anatomical tumor location, and age at diagnosis. Somatic alterations in canonical CRC genes were prevalent, with notable differences in mutation frequencies when compared to NHW samples. Additionally, we uncovered multiple gene amplifications with therapeutic relevance and identified multiple actionable gene fusions. Conclusion: This research enhances our molecular understanding of colorectal cancer in Hispanic and Latino patients, a historically understudied group in cancer genomics. By integrating multi-omics data with ancestry-informed analysis, we highlight novel insights into the biological mechanisms contributing to colorectal carcinogenesis in this population. These findings offer a foundational resource for future studies and support the development of ancestry-aware precision oncology approaches that more accurately reflect population-specific risks and therapeutic targets. Citation Format: Brigette W. Waldrup, Francisco G. Carranza, Yuxin Jin, Yonatan Amzaleg, Mackenzie Postel, David W. Craig, John D. Carpten, Boudoir Salhia, Charite N. Ricker, Julie O. Culver, Carmen E. Chavez, Mariana C. Stern, Lourdes Baezconde-Garbanati, Heinz-Josef Lenz, Enrique I. Velazquez-Villarreal. Colorectal cancer in Hispanic and Latino populations: Genetic similarity and molecular drivers identified via multi-omics analysis [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 A039.