Abstract Background: The incidence of colon cancer is rising more rapidly in patients under 50 years of age (early-onset colon cancer; EOCC) than in any other age group. This trend is likely a consequence of multifactorial causes, including environmental exposures, shifts in lifestyle factors, and expanded use of screening tests which are now recommended for individuals starting at age 45. However, fully defining the genomic landscape and understanding the biological mechanisms driving colorectal cancer in younger patients remains an ongoing effort. Methods: Genomic sequencing data from primary tumors diagnosed as colon adenocarcinoma were obtained from AACR Project GENIE Cohort v18. 0, comprising 7, 633 total patients, and accessed through the Synapse and cBioPortal platforms. Patients were grouped into EOCC (50 years) and traditional-onset colon cancer (≥50 years). To better delineate aging-associated differences, we performed additional analyses using more restrictive age cutoffs of ≤45 years (n=1, 267 patients) and ≥55 years (n=4, 676 patients) for the respective groups. The clinical variable “Age at Which Tumor Sequencing Was Reported (Years) ” was used as a proxy for “age at diagnosis. ” Genes enrichments with fewer than 10 patients were excluded from this analysis. Results: The total cohort included 49. 8% male (n=3801), 46. 7% female (n=3563), and 3. 5% patients of unknown sex/gender (n=269). Evaluation of the rate of patient-level genomic alterations between age groups revealed enrichment of mutations in APC (71. 53% vs 63. 95%, q-value 1. 895e-4), TP53 (70. 74% vs 64. 68%, q-value 6. 248e-3), TCF7L2 (16. 48% vs 12. 46%, q-value 0. 0314), CTNNB1 (9. 6% vs 6. 15%, q-value 4. 746e-3), and MSH2 (6. 29% vs 3. 81%, q-value 0. 0211) in patients with EOCC. In comparison, mutations in BRAF (19. 58% vs 8. 2%, q-value 1. 20e-21), RNF43 (17. 06% vs 9. 07%, q-value 3. 25e-8), ZNRF3 (8. 75% vs 3. 55%, q-value 4. 529e-3), SMARCA4 (9. 2% vs 5. 55%, q-value 7. 461e-3), HLA-B (6. 53% vs 3. 03%, q-value 0. 0269), AMER1 (10. 18% vs 6. 37%, q-value 0. 0321), GNAS (4. 08% vs 2. 25%, q-value 0. 0366), and HNF1A (4. 62% vs 2. 41%, q-value 0. 0211) were enriched in traditional-onset colon cancer. Assessment of individual point mutations revealed enrichment of BRAF V600E (15. 81% vs 4. 42%, q-value 4. 10e-29), KRAS Q61K (0. 94% vs 0. 08%, q-value 0. 0446), and RNF43 G659Vfs*41 (10. 16% vs 3. 93%, q-value 1. 12e-8) in traditional-onset colon cancer. Lastly, assessment of CNA amplifications revealed enrichment of NCOA3 (5. 65% vs 2. 28%, q-value 0. 0276) in EOCC. Conclusion: We have identified novel associations between genomic alterations and patient age in colon cancer using AACR GENIE v. 18, the largest public cancer genomic dataset available to date. Our findings reveal alterations not previously characterized in this age group, suggesting that EOCC may represent a biologically distinct disease entity rather than an earlier manifestation of traditional colon cancer. Further investigation into divergent molecular phenotypes in colon cancer by age at diagnosis is warranted. Citation Format: Johnathan D. DeBetta, Ashani T. Weeraratna, Elizabeth M. Jaffee, Daniel J. Zabransky. Age-stratified insight into genomic alterations in colon adenocarcinoma via AACR GENIE v18. 0 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 C007.
DeBetta et al. (2025) studied this question.