Mutational and co-mutational landscape of early onset colorectal cancer.

INTRODUCTION

Colorectal cancer (CRC) incidence and mortality before 50 have been rising alarmingly in the recent decades.

METHODS

Using a cohort of 10,000 patients, this study investigates the clinical, mutational, and co-mutational features of CRC in early-onset (EOCRC, < 50 years) compared to late-onset (LOCRC, ≥ 50 years).

RESULTS

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 (74% vs. 68%,  < 0.01) and (17% vs. 14%,  = 0.015), while (5% vs. 11%,  < 0.001) and (2.7% vs. 4.1%,  = 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 and mutations in right-sided EOCRC and higher prevalence in MSI-H LOCRC (47% vs. 6.7%,  < 0.001). Additionally, co-occurrence analysis revealed unique mutational networks in EOCRC MSS, including significant co-occurrences of with , , and .

CONCLUSION

This study highlights the significance of age-specific molecular profiling, offering insights into the unique biology of EOCRC and potential clinical applications.