Abstract 1128: Comprehensive multi-omics analysis of colorectal cancer tumors in diverse populations

Abstract Introduction: Colorectal cancer is a leading contributor to cancer-related mortality and health disparities within the Hispanic and Latino community. To uncover the biological and genetic factors underlying these inequities, we conducted an analysis of key colorectal cancer molecular characteristics, focusing on somatic alterations, gene expression and genetic similarity (NASEM's term for genetic ancestry). Methods: As part of the Cancer Moonshot PE-CGS network, we obtained and performed a comprehensive genome-scale analysis of 131 primary CRC Tumor/Normal samples within the Hispanic and Latino population from the Los Angeles area. For comparison, we analyzed 3, 920 Non-Hispanic White (NHW) samples obtained from public databases, including AACR-GENIE. Our methodology included DNA exome sequencing to evaluate somatic mutations, somatic copy number alterations, and genetic similarity, as well as RNA sequencing to investigate differential gene expression, cellular pathways, and gene fusions. Insights from Hispanic and Latino samples were systematically compared with those derived from NHW cohorts. In alignment with the NASEM report and terminology, we adhered to best practices for the use of race, ethnicity, genetic ancestry, and other population descriptors in genetics and genomics research. Results: Our analysis revealed distinct genetic similarity patterns, with a notable prevalence of Peruvian-from-Lima-like (1KG-PEL-like) genetic similarity, as defined by the 1000 Genomes Project. These patterns correlated with microsatellite stability (MSI) status, age at diagnosis, and tumor location. Significant mutations were identified in key colorectal cancer genes, including APC, TP53, and KRAS. Comparative analyses highlighted CRC-related genes with significant differences between Hispanic and Latino samples and NHW cohorts. Drug-targetable amplifications were also identified, while gene fusion analyses uncovered targetable genes such as ALK, FGFR1, RAF1, and PTPRK. Notably, PTPRK was observed in samples with the highest 1KG-PEL-like genetic similarity proportions. Conclusion: This study advances the molecular profiling of colorectal cancer in Hispanics and Latinos, addressing an underrepresented population in cancer research. As one of the first Cancer Moonshot projects focused on CRC in Hispanics and Latinos with a substantial sample size and among the pioneering efforts to utilize multi-omics for molecular characterization, it sets a significant precedent. Genetic similarity is identified as a critical factor in colorectal carcinogenesis, providing essential insights into the biological drivers of cancer health disparities. By establishing a comprehensive framework for analyzing this underserved group, this research lays the groundwork for future studies, fostering advancements in precision medicine and supporting the development of tailored therapeutic strategies. Citation Format: Brigette 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. Comprehensive multi-omics analysis of colorectal cancer tumors in diverse populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1128.