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