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. 2025 Feb;30(1):64-76.
doi: 10.1080/1354750X.2024.2447089. Epub 2025 Jan 9.

Mutational and co-mutational landscape of early onset colorectal cancer

Jumanah Yousef Alshenaifi  1 , Guglielmo Vetere  1 , Giulia Maddalena  1 , Mahmoud Yousef  1 , Michael G White  2 , John Paul Shen  1 , Eduardo Vilar  1 , Christine Parseghian  1 , Arvind Dasari  1 , Van Karlyle Morris  1 , Ryan Huey  1 , Michael J Overman  1 , Robert Wolff  1 , Kanwal P Raghav  1 , Jason Willis  1 , Kristin Alfaro  1 , Andy Futreal  3 , Y Nancy You  2 , Scott Kopetz  1
Affiliations

Mutational and co-mutational landscape of early onset colorectal cancer

Jumanah Yousef Alshenaifi et al. Biomarkers. 2025 Feb.

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.

Keywords: APC; Early-onset colorectal cancer; NGS; TP53; late-onset colorectal cancer; next-generation sequencing.

Plain language summary

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.

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Conflict of interest statement

CONFLICTS OF INTEREST: Disclosures are outside the scope of the work that was submitted. However, Dr. Kopetz has ownership interest in Lutris, Frontier Medicines, Navire and is a consultant for Genentech, Merck, Boehringer Ingelheim, Bayer Health, Pfizer, Mirati Therapeutics, Flame Biosciences, Carina Biotech, Frontier Medicines, Replimune, Bristol-Myers Squibb-Medarex, Amgen, Tempus, Harbinger Oncology, Zentalis, AVEO, Tachyon Therapeutics, Agenus, Revolution Medicines, Kestrel Therapeutics, Roche, Arcus Biosciences, AstraZeneca Pharmaceuticals, BeiGene, Clasp Therapeutics, Cytovation, Dewpoint Therapeutics, Marengo Therapeutics, SageMedic, Servier, Sibylla, T-Cypher Bio, XAIRA, AmMax Bio, Ikena, and receive research funding from, Guardant Health, Genentech/Roche, EMD Serono, Amgen, Lilly, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, BridgeBio, Zentalis, BioMed Valley, Johnson & Johnson, BMS, Cardiff, Jazz Pharmaceuticals, Frontier Medicines. Dr Huey reported personal fees from Clinical Care Targeted Communications, Vizient, and Aptitude Health outside the submitted work. Dr Morris reported institutional research funding from Bristol Myers Squibb, Pfizer Research, REDX Pharma, BioNTech, and Regeneron outside the submitted work. Dr Vilar reported research funds and/or advisory board fees from Guardant Health, Nouscom, Rising Tide Foundation, and Recursion Pharma outside the submitted work. Dr Shen reported research funding from Celsius Therapeutics, BostonGene, NaDeNo Nanoscience, and Engine Biosciences. No other disclosures were reported.

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