Age-associated mutation patterns and a potential therapeutic opportunity in early-onset colorectal cancer.

197 Background: Colorectal cancer (CRC) is increasingly diagnosed in younger adults, with evidence that early-onset cases differ in the spectrum of prevalent gene mutations compared to older individuals. To evaluate how these age-related differences may inform testing guidelines and therapeutic development, we examined mutation rates of the most prevalent gene mutations across four age-stratified cohorts. Methods: Clinicogenomic data were obtained from MSK-CHORD and China Pan-Cancer cohorts available in cBioPortal. A total of 6762 samples were analyzed. Mutation frequencies for a comprehensive panel of the 100 most prevalent colorectal cancer genes were compared across four age groups: 18-29 (n=79), 30-39 (n=402), 40-49 (n=1064), and ≥50 (n=5217) using chi-squared analysis. False discovery rate (FDR) correction for multiple comparisons was performed using Benjamini-Hochberg procedure. Results: Significant variation in mutation frequency across age groups was seen in 22 genes, including APC, SMAD4, CTNNB1, LRP1B, BRAF, KMT2A, EPHA5, FAT3, STED2, TSC1, and POLE. APC mutations increased with age and were seen in 49.4% of patients in the 18-29 group, 69.7% in 30-39, 73.3% in 40-49, and 75.25% of patients ≥50 (p <0.001, FDR <0.001). The oldest cohort was over three times more likely to have an APC mutation than the youngest (odds ratio = 3.74 95% CI 2.44-5.74, p<0.001). In contrast, SMAD4 mutations were twice as common in the youngest age group at 31.6% compared to those over 40, with a prevalence of 17.29% in patients 40-49, and 18.84% in patients over 50 (odds ratio = 2.03 95% CI 1.26-3.27, p <0.001, FDR <0.001). POLE mutations peaked in the 30-39 age group with a prevalence of 10.7% compared to 6.3% in patients aged 18-29, 4.9% in those 40-49, and 5.9% in patients ≥50 (p <0.001, FDR <0.001). Individuals in the 30-39 group nearly twice as likely to carry a POLE mutation compared to those over 40 (odds ratio = 1.96 95% CI 1.41-2.74, p <0.001). Conclusions: Lower prevalence of APC mutations and increased SMAD4 mutations in younger individuals suggests that early-onset CRC may represent a distinct biological subtype. Enrichment of POLE mutations in younger patients highlights the importance of expanded molecular profiling in early-onset CRC, which could help identify patients most likely to benefit from immunotherapy and advance personalized treatment strategies in colorectal cancer. Together, these findings reinforce the need to approach early-onset CRC as a distinct biological entity and ensure that appropriate molecular assays are incorporated to guide care.