Abstract B005: Comparative genomic analysis between early-onset and average-onset colorectal cancer patients at the Cleveland Clinic

Abstract The etiology underlying the alarming rise in early-onset colorectal cancer (EOCRC; age at diagnosis 50 years) remains largely unknown. Studies of the genomic and molecular landscapes of EOCRC tumors may elucidate unique mutational features potentially linked to novel environmental exposures and provide clues about driver events in cancer development and progression. To date, conflicting evidence in the literature exists regarding whether or not EOCRCs have distinct genomic and tumor microenvironment characteristics or have more aggressive disease biology than average-onset colorectal cancers (AOCRC; age at diagnosis ≥ 50 years). Here, we compared clinical characteristics and somatic genomic features of tumors from patients with EOCRC and AOCRC whose tumors underwent standard of care next generation sequencing at the Cleveland Clinic, a tertiary cancer care center, between 2019 and 2025. Sequencing was completed using the Caris (tumor only) or Tempus (paired tumor and normal) platforms, and data were compiled into a Cleveland Clinic-specific cBioPortal instance, linked to the local tumor registry, and analyzed on a deidentified basis. Five hundred forty-eight patients with a colorectal cancer diagnosis (112 EOCRC and 436 AOCRC) had data available through this platform. Of those, the average age at diagnosis was 60. 6 (SD: 13. 4), and 44% were female. Eighty percent were of White race (13% Black) and 7. 2% were of Hispanic ethnicity. Whole exome sequencing was conducted on a combination of primary tumors (62. 2%) and metastatic lesions (37. 7%). As anticipated, the majority of patients had metastatic disease (73%) at diagnosis, as compared to 5. 7% stage I, 5. 5% stage II, and 16% stage III. The overall proportion of rectal cancer was higher in EOCRC than AOCRC (35% vs. 27%) ; however, this difference was not statistically significant after adjusting for sex (P=0. 17). Advanced stage disease at diagnosis was similar between average and early onset (90% vs. 88%; P=0. 30), likely due to insurance coverage for clinical sequencing in this patient population. After adjusting for sex, age of onset was not associated with MSI-H status (P=0. 50). No significant difference in tumor mutational burden was observed between EOCRC and AOCRC (P=0. 50). In univariate analyses, EOCRC tumors were significantly enriched for mutations in KRAS (OR=2. 01, 95% confidence interval (CI) 1. 23-3. 27, FDR P=0. 036) and PIK3CA (OR=2. 42, CI 1. 18-4. 85, FDR P=0. 042). APC (OR=1. 63, FDR P=0. 078) and TP53 (OR=1. 57, FDR P=0. 089) showed trends toward higher prevalence of mutations among EOCRC tumors, while BRAF, SMAD4, LRP1B, and SYNE1 did not show significant differences between age groups. This analysis suggests potential differences in the frequency of common driver mutations between EOCRC and AOCRC cases with primarily advanced stage disease. Citation Format: Stephanie L. Schmit, Daniel Sobieski, Ying Ni, Jacob Mansell, Camila Gonzalez, Sarah McClaren, Alok A. Khorana, David Liska. Comparative genomic analysis between early-onset and average-onset colorectal cancer patients at the Cleveland Clinic 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 B005.