Comprehensive multi-omics characterization of colorectal cancer in a community catchment population

Introduction: Colorectal cancer (CRC) remains a leading cause of cancer mortality and disproportionately affects Hispanic and Latino populations in the United States, who remain underrepresented in genomic research. To address this gap, we performed a comprehensive multi-omics analysis to identify biological and genetic factors contributing to CRC disparities, including somatic alterations, gene expression programs, and genetic similarity (NASEM terminology for genetic ancestry). Methods: Through the Cancer Moonshot PE-CGS Network, we analyzed 204 paired primary CRC tumor/normal samples from individuals in the Los Angeles catchment area. For comparison, 3,920 Non-Hispanic White (NHW) CRC samples were evaluated using public datasets, including AACR Project GENIE. DNA exome sequencing was used to assess somatic mutations, copy number alterations, gene fusions, and genetic similarity. RNA sequencing profiled differential gene expression, pathway activity, and immune signatures. Analyses followed NASEM best practices for the use of race, ethnicity, and genetic ancestry in genomics research. Results: Genetic similarity analysis identified a high prevalence of Peruvian-from-Lima-like (1KG-PEL-like) similarity among Hispanic and Latino patients. Higher 1KG-PEL-like similarity was associated with microsatellite stability status, younger age at diagnosis, and left-sided tumor location. Somatic analysis revealed significant alterations in APC, TP53, KRAS, and other CRC-associated genes, with notable differences in mutation frequencies compared with NHW samples. Copy-number profiling identified amplifications in drug-targetable loci, and fusion analysis detected clinically relevant events including ALK, FGFR1, RAF1, and enriched PTPRK fusions in tumors with the highest 1KG-PEL-like similarity. Transcriptomic analyses demonstrated distinct pathway activation and immune-related expression programs compared with NHW CRCs. Conclusion: This study provides one of the most comprehensive multi-omics characterizations of CRC in an underrepresented population. By integrating genetic similarity with somatic, structural, and transcriptional features, these findings reveal biologically meaningful patterns that may contribute to CRC disparities. This work establishes a foundational framework for future investigations and supports the development of ancestry-informed precision oncology strategies.