PhD Scientific Days 2025

Poster Session II. - E: Pathological and Oncological Sciences

Age-related differences in the mutational landscape of colorectal cancer

Name of the presenter

Bende Zsanett

Institute/workplace of the presenter

Department of Bioinformatics, Semmelweis University

Authors

Zsanett Bende¹, Janos Tibor Fekete¹

1: Department of Bioinformatics, Semmelweis University

Text of the abstract

Age-related differences in the mutational landscape of colorectal cancer
Zsanett Bende, János Tibor Fekete
Department of Bioinformatics, Semmelweis University

Introduction:
Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50, a group traditionally considered low risk. The rising incidence of early-onset CRC (EOCRC) suggests biological differences compared to late-onset CRC (LOCRC), potentially impacting prognosis and therapeutic response.
Aims:
To evaluate whether the mutational landscape of CRC differs between patients younger than 50 and those aged 50 or older, and to identify potential age-specific genomic and prognostic patterns.
Methods:
Genomic and clinical data from the MSK-CHORD cohort were analyzed via cBioPortal. Somatic mutations were obtained from the MSK-IMPACT sequencing assay covering protein-coding exons of 468 genes. All variants within these exonic regions were included. Mutation frequencies were compared between EOCRC (<50 years) and LOCRC (≥50 years) using Fisher’s exact test with false discovery rate (FDR) correction. Genes with FDR < 0.05 were further analyzed for association with overall survival (OS) using univariable Cox models in the full cohort and age-stratified subgroups.
Results:
A total of 5,543 patients were included (EOCRC: 1,475; LOCRC: 4,066). EOCRC cases had lower tumor mutational burden (median: 5.74 vs. 6.56 mutations/Mb, p = 7.14×10⁻¹⁹) and less frequent MSI-high status (8.5% vs. 11.6%, p = 0.0032). Forty-eight genes showed significant mutation frequency differences by age, including RNF43, BRAF, and TP53, all enriched in LOCRC. No gene was more frequent in EOCRC. In survival analysis, multiple genes showed age-specific prognostic impact. Mutations in RNF43, BRD4, CASP8, GNAS, HLA-B, and TCF7L2 were significantly associated with improved OS in EOCRC but showed weaker or no effect in LOCRC. Conversely, BRAF mutation was linked to poorer survival in EOCRC (HR = 1.44, p = 0.0071), but not in LOCRC. Several genes (RECQL, FOXP1) were prognostic only in LOCRC. TP53 mutation was consistently associated with worse OS in both groups.
Conclusion:
The frequency and prognostic impact of somatic mutations in CRC vary by age. These findings underscore the need for age-specific molecular profiling and support stratified prognostic assessment in clinical practice and future therapeutic strategies.
Funding: No funding was used.