TY - JOUR
T1 - Exploring the Somatic Mutation Landscape of T4N0
T2 - A Comparative Perspective on Late Stage II and Stage III Colon Cancer
AU - Otohinoyi, David
AU - Pavleszek, Katherine E.
AU - Alexandra Dooley, Danielle
AU - Carr, Brian T.
AU - Mabry, Triston L.
AU - Hicks, Chindo
AU - Nfonsam, Valentine N.
N1 - Publisher Copyright:
© The ASCRS 2025.
PY - 2025/7/1
Y1 - 2025/7/1
N2 - 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 to 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 the Fisher 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 data sets. 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 contribute 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. See Video Abstract.
AB - 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 to 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 the Fisher 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 data sets. 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 contribute 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. See Video Abstract.
KW - Bioinformatics
KW - Colon cancer
KW - Genetics
KW - Mutation
KW - T4N0
UR - https://www.scopus.com/pages/publications/105003170133
UR - https://www.scopus.com/pages/publications/105003170133#tab=citedBy
U2 - 10.1097/DCR.0000000000003721
DO - 10.1097/DCR.0000000000003721
M3 - Article
C2 - 40192132
AN - SCOPUS:105003170133
SN - 0012-3706
VL - 68
SP - 845
EP - 854
JO - Diseases of the Colon and Rectum
JF - Diseases of the Colon and Rectum
IS - 7
ER -