Mutational and co-mutational landscape of early onset colorectal cancer
Jumanah Alshenaifi, Guglielmo Vetere, Giulia Maddalena, Mahmoud Yousef, Michael G. White, John Paul Shen, Eduardo Vilar, Christine M. Parseghian, Arvind Dasari, Van K. Morris, Ryan Huey, Michael J. Overman, Robert A. Wolff, Kanwal Raghav, Jason Willis, Kristin D Alfaro, Andy Futreal, Y. Nancy You, Scott Kopetz
Abstract
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 TP53 (74% vs. 68%, p < 0.01) and SMAD4 (17% vs. 14%, p = 0.015), while BRAF (5% vs. 11%, p < 0.001) and 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 < 0.001). Additionally, co-occurrence analysis revealed unique mutational networks in EOCRC MSS, including significant co-occurrences of FBXW7 with NOTCH3, RB1, and PIK3R1.Conclusion This study highlights the significance of age-specific molecular profiling, offering insights into the unique biology of EOCRC and potential clinical applications.