Abstract PR012: Transcriptomic and pathway analyses patterns in early-onset and late-onset microsatellite stable colorectal cancer: Results from the ORIEN Network

Abstract Introduction: Although ∼20% of early-onset colorectal cancer (EOCRC, age at diagnosis 50y) cases are due to germline mutations, the etiology of the majority of EOCRC cases remains poorly understood. EOCRC differs molecularly from late-onset colorectal cancer (LOCRC, age at diagnosis 70y), with EOCRC tumors more frequently exhibiting high-grade histology, immune-related signatures, and microsatellite instability, while LOCRC is marked by DNA damage and oxidative stress pathways. Although consensus molecular subtypes (CMS) offer a framework for classification, they do not fully explain the rising EOCRC incidence, highlighting the need for integrative multiomic approaches to uncover underlying genetic, epigenetic, and environmental drivers for EOCRC. Methods: We leveraged genomic, transcriptomic, and clinical data from 1, 135 sporadic microsatellite stable colorectal cancer (CRC) patients enrolled in the Total Cancer Care protocol and included in the Oncology Research Information Exchange Network (ORIEN) Avatar program across seven U. S. cancer centers, using standardized protocols for biospecimen collection, sequencing, and data harmonization. Whole exome sequencing (WES) and transcriptomic profiling (RNA-Seq) was conducted using standardized pipelines, followed by normalization and filtering. We characterized biological differences across EOCRC and LOCRC using differential expression, molecular subtyping, immune deconvolution, survival analysis, and integrated pathway analyses combining RNA-seq and WES data. Results: Our cohort included 27. 8% EOCRC, 53. 5% average-onset (50-69y) and 18. 9% LOCRC cases. EOCRC patients were more likely to present with rectal tumors (24% vs. 14%), advanced stage (75% vs. 57%), and receive treatments at a higher proportion (radiotherapy: 35% vs. 23%; adjuvant therapy: 51% vs. 37%) compared to LOCRC. No significant differences were observed in common CRC mutations or tumor mutational burden. EOCRC cases were significantly enriched for the mesenchymal CMS4 subtype and depleted in CMS2 and CMS3 (p 9. 46 × 10-6), though 5-year survival did not differ by CMS (p-value=0. 23). Notably, we observed that EOCRC cases with CMS2 or CMS4 were more likely to be overweight (BMI = 25kg/m2) as compared to LOCRC (OR 2). Transcriptomic analysis identified 328 differentially expressed genes (306 up-regulated and 22 down-regulated in EOCRC) ; GSEA analysis showed enrichment of Hedgehog and calcium signaling pathways (FDR 0. 1) in EOCRC. Conclusions: This comparison of EOCRC and LOCRC cases demonstrates clear differences in CMS subtypes, reveals specific associations with environmental factors, and suggests that calcium channel signaling and hedgehog signaling may play a crucial role in the development and progression of EOCRC compared to LOCRC. Citation Format: Sheetal Hardikar, Griffin Caryotakis, David A. Nix, Aaron Atkinson, Jamie Teer, Vaia Florou, Andreana Holowatyj, Michelle L. Churchman, David M. McKean, Phaedra Agius, Bodour Salhia, Ning Jin, Daniel Spakowicz, Micha Cavnar, Emily Baiyee. Toegel, Tiago Biachi de Castria, Patrick M. Boland, Ahmad Tarhini, Bryan P. Schneider, Matthew Reilley, Deepak Vadehra, Michele M. Gage, Howard Colman, Courtney Scaife, Jessica N. Cohan, Biljana Gigic, Adetunji Toriola, Christopher I. Li, Jane Figueiredo, Dorotha Byrd, David Shibata, Cornelia M. Ulrich, Aik Choo Tan, Erin M. Siegel. Transcriptomic and pathway analyses patterns in early-onset and late-onset microsatellite stable colorectal cancer: Results from the ORIEN Network abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr PR012.