Exploring the Somatic Mutation Landscape of T4N0: A Comparative Perspective on Late Stage 2 and Stage 3 Colon Cancer

Document Type

Article

Publication Date

4-7-2025

Publication Title

Diseases of the Colon and Rectum

Abstract

BACKGROUND: Among the facets of colon cancer pathogenesis is the survival paradox between T4N0 (stage II) colon cancer and anyTN1 (stage III) colon cancer. There are limited genomic studies investigating why a T4N0 disease is deemed worse than stage III colon cancer OBJECTIVE: We demonstrate a multifaceted approach in unraveling the genomic intricacies of T4N0 colon cancer and how it differs from T123N0 and anyTN1 colon cancer using somatic mutation information. DESIGN: Retrospective study of somatic mutations and their prognostic impact on survival. SETTINGS: Conducted using The Cancer Genome Atlas and National cBioPortal for Cancer Genomics. PATIENTS: We stratified our samples based on TNM staging: T4N0, T123N0 and anyTN1 MAIN OUTCOME MEASURES: We compared mutation frequency between groups using fishers exact test at P ≤ 0.05. We performed pathway analysis to map biological networks enriched with somatic mutations. We investigated somatic mutation interaction and validated our results with Kaplan-Meier survival analysis on independent datasets. RESULTS: We observed 30 significantly differentially mutated genes that are unique to T4N0 colon cancer after T123N0 and anyTN1 comparisons. Among these genes, DIDO1, CACNA1B and ALMS1 showed somatic mutation interaction in a co-occurring pattern with other mutated genes. Pathway analysis revealed Ephrin B signaling, Nitric oxide signaling, and calcium signaling to be enriched with mutations and contributory to T4N0 pathogenesis. Survival analysis further substantiated our findings. LIMITATIONS: Retrospective study and patient numbers. CONCLUSIONS: There are patterns of somatic mutation in T4N0 colon cancer tumors that are significantly absent in T123N0 and anyTN1 colon tumors. Somatic mutation interaction highlighted the role of DIDO1, CACNA1B and ALMS1 in T4N0 pathogenesis which contained appreciable mutations that were predicted to be severe. Among these genes, DIDO1 was associated with a decrease in survival.

PubMed ID

40192132

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