Mutational and Co-Mutational Landscape of Early Onset Colorectal Cancer

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

doi:10.1080/1354750X.2024.2447089

Mutational and Co-Mutational Landscape of Early Onset Colorectal Cancer

Biomarkers. 2025 Jan 6:1-19. doi: 10.1080/1354750X.2024.2447089. Online ahead of print.

Authors

Jumanah Yousef Alshenaifi¹, Guglielmo Vetere¹, Giulia Maddalena¹, Mahmoud Yousef¹, Michael G White², John Paul Shen¹, Eduardo Vilar¹, Christine Parseghian¹, Arvind Dasari¹, Van Karlyle Morris¹, Ryan Huey¹, Michael J Overman¹, Robert Wolff¹, Kanwal P Raghav¹, Jason Willis¹, Kristin Alfaro¹, Andy Futreal³, Y Nancy You², Scott Kopetz¹

Affiliations

¹ Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Colon & Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
³ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

PMID: 39761813
DOI: 10.1080/1354750X.2024.2447089

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; Late-onset colorectal cancer; NGS; Next-generation sequencing; TP53.

Plain language summary

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 TP53 and lower APC mutations, highlight the importance of developing age-adapted screening protocols and prognostic tools to detect and manage EOCRC more effectively.