Mutational and co-mutational landscape of early onset colorectal cancer

Colorectal cancer (CRC) incidence and mortality before 50 have been rising alarmingly in the recent decades. Using a cohort of 10,000 patients, this study investigates the clinical, mutational, and co-mutational features of CRC in early-onset (EOCRC, EOCRC was associated with a higher prevalence of Asian and Hispanic patients, rectal or left-sided tumors (72% vs. 59%), and advanced-stage disease. Molecular analyses revealed differences in mutation patterns, with EOCRC having higher frequencies of TP53 (74% vs. 68%, p SMAD4 (17% vs. 14%, p = 0.015), while BRAF (5% vs. 11%, p NOTCH1 (2.7% vs. 4.1%, p = 0.01) mutations were more prevalent in LOCRC. Stratification by tumor site and MSI status highlighted significant location- and age-specific molecular differences, such as increased KRAS and CTNNB1 mutations in right-sided EOCRC and higher BRAF prevalence in MSI-H LOCRC (47% vs. 6.7%, p FBXW7 with NOTCH3, RB1, and PIK3R1. This study highlights the significance of age-specific molecular profiling, offering insights into the unique biology of EOCRC and potential clinical applications. The unique mutational and co-mutational patterns identified in early-onset colorectal cancer (EOCRC) highlight the necessity for age-specific molecular profiling. These findings can guide tailored therapeutic approaches and improve precision medicine strategies for younger patients with colorectal cancer.The raised prevalence of advanced-stage disease and unique molecular features in EOCRC, such as higher TP53 and lower APC mutations, highlight the importance of developing age-adapted screening protocols and prognostic tools to detect and manage EOCRC more effectively. The unique mutational and co-mutational patterns identified in early-onset colorectal cancer (EOCRC) highlight the necessity for age-specific molecular profiling. These findings can guide tailored therapeutic approaches and improve precision medicine strategies for younger patients with colorectal cancer. The raised prevalence of advanced-stage disease and unique molecular features in EOCRC, such as higher TP53 and lower APC mutations, highlight the importance of developing age-adapted screening protocols and prognostic tools to detect and manage EOCRC more effectively.