MUC Gene Abnormalities in Sporadic and Hereditary Mucinous Colon Cancers with Microsatellite Instability

Chiara Pastrello,Alessandra Viel,Roberto Sigon,Mara Fornasarig,Manuela Santarosa,Tiziana Perin,Mauro Boiocchi,Giuseppe Giannini

doi:10.1155/2005/370908

Abstract

Aim of this study was verifying whether mucin producing colon cancers (CRCs) could develop through a molecular pathway involving microsatellite instability (MSI) and MUC gene alterations. Out of 49 CRCs expressing variable amounts of mucin, 22 (44.9%) were MSI-H and 5 (10.2%) were MSI-L. MUC genes were analyzed by Southern blotting and extra bands were evident in the Variable Number Tandem Repetition (VNTR) regions of MUC2 (5 cases) and MUC5AC (2 cases), but not MUC1 and MUC4 genes. Since the somatic VNTR abnormalities were detected in 6 MSI-H and in 1 MSI-L tumors, they seem to be peculiar of mismatch repair defective CRCs. Our finding suggests that alteration and/or loss of structurally normal MUC genes may be an important step in the neoplastic molecular pathway of a subset of CRCs and that mutations involving VNTR repetitive sequences may exist in MSI tumors as a direct and/or indirect consequence of an inefficient MMR system.

Highlights

Several studies have been carried out to elucidate the molecular pathways involved in the multistep process of the colorectal carcinogenesis and, at present, the pathogenesis of colon cancer (CRC) is one of the best known
HinfI digestion could be applied to all 49 cases for the analysis of MUC1, MUC2 and MUC5AC genes, whereas PvuII restriction was limited to the study of MUC4 and MUC5AC genes in the 40 tumors for which sufficient amount of DNA was available
The MUC analysis was restricted to 4 genes coding mucins that are variably produced in gastrointestinal normal epithelia and whose expression appears deregulated in colon tumors [1,3,22]

Summary

Introduction

Several studies have been carried out to elucidate the molecular pathways involved in the multistep process of the colorectal carcinogenesis and, at present, the pathogenesis of colon cancer (CRC) is one of the best known. CRCs developing in Hereditary Non Polyposis Colorectal Cancer (HNPCC) patients with constitutional mutations in MSH2 or MLH1 genes always display the MSI phenotype. Pastrello et al / MUC gene abnormalities in sporadic and hereditary mucinous colon cancers with Microsatellite Instability of the MLH1 gene and this phenomenon concerns the majority of the MSI sporadic cases [13,14]. Each of these units has a specific length and sequence, and in several MUC genes their repetitions vary individually according to a genetic polymorphism [9,20] These Variable Number Tandem Repetition (VNTR) regions codify for the major portion of the peptide cores that are heavily glycosylated and display antigenic properties. Data on mucin production were collected by consultation of the pathologic reports, and tumors were classified as ++ (10 cases reported as mucinous histology or with prevalent mucinous components or 50% mucus), + (28 cases with partial/focal mucinous components or

Molecular analyses

Patients and tissues

MUC genes

Conclusion