ABSTRACT
BACKGROUND: The aim was to determine the values of p53 tumour expression and microsatellite instability (MSI) phenotype to predict benefit from adjuvant chemotherapy of colon cancer by 5-fluorouracil and leucovorin (FL) alone or with oxaliplatin (FOLFOX). PATIENTS AND METHODS: This retrospective study included 233 unselected patients with stage III colon cancer treated by FL (n = 124) or FOLFOX (n = 109). The impact of p53 expression and MSI on disease-free survival (DFS) was defined using univariate and multivariate analyses. A Cox proportional hazards model was specifically designed to evaluate the interaction between chemotherapy and these genetic alterations. RESULTS: In univariate analyses, addition of oxaliplatin significantly improved DFS provided that tumour overexpressed p53 [hazard ratio (HR) 0.39; 95% confidence interval (CI) 0.19-0.82; P = 0.01] or displayed MSI phenotype (HR 0.17; 95% CI 0.04-0.68; P = 0.01). In multivariate analyses, p53 was confirmed as an independent factor predictive of benefit from FOLFOX (P = 0.03), while the interaction of MSI with chemotherapy could not be determined in the absence of relapse in the MSI group treated with FOLFOX. CONCLUSION: Our observations indicate that MSI status and p53 expression may influence the impact of oxaliplatin on adjuvant treatment of stage III colon cancer patients.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Microsatellite Instability , Tumor Suppressor Protein p53/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Retrospective Studies , Tumor Suppressor Protein p53/physiologySubject(s)
Adaptor Proteins, Signal Transducing/biosynthesis , DNA Mismatch Repair , Lymphoma, B-Cell, Marginal Zone/physiopathology , Microsatellite Instability , MutS Homolog 2 Protein/biosynthesis , Nuclear Proteins/biosynthesis , Stomach Neoplasms/physiopathology , Humans , Lymphoma, Non-Hodgkin/physiopathology , MutL Protein Homolog 1 , Retrospective StudiesABSTRACT
TCF-4 is the main effector of the Wnt/Wingless signalling pathway. As with other TCF/LEF factors, numerous alternative splicings at its 3' end affect its expression. Such a mechanism leads to the synthesis of numerous TCF-4 isoforms among which some contain binding domains for CtBP, an ubiquitous transcriptional corepressor. Of interest, we described a frequent TCF-4 frameshift mutation in mismatch-repair deficient colorectal cancers (MSI-H cancers) that leads to the selective loss of TCF-4 isoforms with CtBP binding abilities. We provide here data that argue for a partial colocalization of CtBP with TCF-4 isoforms containing CtBP binding domains in cellulo, and for a functional role of CtBP in repressing TCF-4 mediated transcription. We also demonstrate that such a colocalization is not observed in MSI-H colorectal cancer cells that harbour the TCF-4 frameshift mutation, and that CtBP is not able to repress TCF-4-mediated transcription in this context. Taken together, our results strongly suggest that CtBP would play a role in regulating TCF-4 mediated transcription upon its binding with some TCF-4 isoforms encoded by alternatively spliced mRNA. They also suggest a role for TCF-4 frameshift mutation during MSI-H colorectal tumour progression, by regulating the relative proportion of the different TCF-4 isoforms.