Abstract 3742: Multi-omics analysis of MYC gene and WNT signaling pathway alterations in early-onset colorectal cancer in Hispanic/Latino patients, enhanced with spatial transcriptomics approaches

Introduction: Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths globally. While CRC rates have stabilized or decreased in affluent nations, cases among younger individuals are rising, particularly in Hispanic/Latino (H/L) populations, who show the highest increase in early-onset (<50) CRC (EOCRC) in the U.S. Despite this, H/L populations remain underrepresented in molecular profiling studies. Key aspects of CRC molecular characterization, critical to tumorigenesis, include the MYC proto-oncogene and the WNT signaling pathway. Methods: We performed a multi-omics analysis of 67 CRC Tumor/Normal samples —30 early-onset (EO) and 37 late-onset (LO)— from Hispanic/Latino (H/L) patients as part of the Cancer Moonshot Initiative's Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Molecular characterization involved whole-exome sequencing to identify somatic mutations, somatic copy number alterations (SCNAs), and both global and local genetic similarities (a term recommended by NASEM for genetic ancestry). RNA sequencing was used to assess differential gene expression, cellular pathways, and gene fusions. Finally, EO H/L samples were compared to public data such as AACR Project GENIE dataset, specifically from 3,578 Non-Hispanic White (NHW) cohorts, to provide broader context. As well, we incorporated three CRC samples with spatial transcriptomic (ST) data from the 10x Genomics database, analyzed using bioinformatics tools and integrated with clinical and genomic data —translational research. Following NASEM guidelines, we adhered to best practices for population descriptors in genetics and genomic research. Results: EO samples, with a median 60% genetic similarity to the 1000 Genomes Project Peruvian-in-Lima (1KG-PEL) population, showed significant mutations in 41 WNT pathway genes, including APC, TCF7L2, DKK1, DKK2, FZD10, and LRP5. Samples with DKK1 and DKK2 mutations had the highest 1KG-PEL-like proportion (79%). Four key genes—DKK1, DKK2, FZD10, and LRP5—were significant in both risk association and differential expression analyses between H/L and NHW cohorts. EO tumors displayed unique SCNAs and gene expression profiles, notably in MYC and drug-targetable WNT pathway genes, compared to LO tumors. Also, a novel WNT gene fusion, RSPO3, linked to increased WNT signaling, was identified in EO tumors. Lastly, ST analysis uncovered distinct functional patterns of WNT-related genes across tumor components, including cancerous, immune, and stromal regions. Conclusion: This study characterizes EOCRC in the H/L population, uncovering unique genomic and transcriptomic features that inform precision oncology and highlight the importance of addressing cancer health disparities through multi-omics analysis. Citation Format: Francisco Gutierrez Carranza, Brigette Waldrup, Yuxin Jin, Yonatan Amzaleg, Mackenzie Postel, David W. Craig, John D. Carpten, Salhia Badour, Daisy Hernandez, Natalia Gutierrez, Charite N. Ricker, Julie O. Culver, Carmen E. Chavez, Mariana C. Stern, Lourdes Baezconde-Garbanati, Heinz-Josef Lenz, Enrique I. Velazquez-Villarreal. Multi-omics analysis of MYC gene and WNT signaling pathway alterations in early-onset colorectal cancer in Hispanic/Latino patients, enhanced with spatial transcriptomics approaches [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 3742.