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, &lt; 50 years) compared to late-onset (LOCRC, ≥ 50 years). 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 <i>TP53</i> (74% vs. 68%, P &lt; 0.01) and <i>SMAD4</i> (17% vs. 14%, P = 0.015), while <i>BRAF</i> (5% vs. 11%, P &lt; 0.001) and <i>NOTCH1</i> (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 <i>KRAS</i> and <i>CTNNB1</i> mutations in right-sided EOCRC and higher <i>BRAF</i> prevalence in MSI-H LOCRC (47% vs. 6.7%, P &lt; 0.001). Additionally, co-occurrence analysis revealed unique mutational networks in EOCRC MSS, including significant co-occurrences of <i>FBXW7</i> with <i>NOTCH3</i>, <i>RB1</i>, and <i>PIK3R1</i>. This study highlights the significance of age-specific molecular profiling, offering insights into the unique biology of EOCRC and potential clinical applications. 1. 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. 2. The raised prevalence of advanced-stage disease and unique molecular features in EOCRC, such as higher <i>TP53</i> and lower <i>APC</i> mutations, highlight the importance of developing age-adapted screening protocols and prognostic tools to detect and manage EOCRC more effectively.