de Leon, M. Ponz; Scarselli, A.; Benatti, P.; Roncucci, L.; Ponti, G.; Losi, L.; Pedroni, M.; Borghi, F.; Menigatti, M.; Di Gregorio, C.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA40
Academic Journal
The large majority of mutations causing hereditary nonpolyposis colorectal cancer (HNPCC) occurs in hMLH1 or hMSH2 genes, but recent observations have shown that other genes can be involved. The aim of this study was to evaluate the role of hMSH6 gene in HNPCC, through an immunohistochemical approach. 28 colorectal cancer patients with clinical diagnosis of HNPCC or suspected HNPCC were selected. Immunohistochemical studies of hMSH6, hMLH1, and hMSH2 were carried out in paraffin embedded tumour samples. Immunoperoxidase staining was carried out with the NEX-ES, Automatic System. Monoclonal antibodies to hMLH1 and hMSH2 proteins were used at 1:40 dilution; monoclonal antibody to hMSH6 protein was used at 1:2000 dilution. Each tumour sample was tested for microsatellite instability (MSI). Immunohistochemical expression of hMSH6 lacked in 7 of 28 tumours. In 4 cases, absence of hMSH2 expression was associated. The patients (mean age 56.6 years) were all affected by rightsided colon cancer, frequently mucinous and MSI+. Three patients were from HNPCC families fulfilling Amsterdam Criteria I or II. In 2 cases Muir-Torre syndrome (MTS) could be diagnosed, whereas the other 2 were suspected HNPCC. In almost all the pedigrees, an excess of extracolonic tumours was observed: interestingly, in both MTS patients, colorectal cancers and sebaceous dermatologic lesions showed the same immunohistochemical pattern. The complete gene sequencing was carried out in 3 of 7 patients: two hMSH6 and one hMSH2 frameshift mutations leading to a stop codon with a truncated protein were detected. In conclusion, hMSH6 mutations could characterise a subset of families with hereditary colorectal cancer. Altered hMSH6 expression (even if often associated with lack of hMSH2 protein), MSI+, proximal Iocalisation, later age at diagnosis, and the association with extracolonic tumours, seem to be features of suspicion for the presence of hMSH6 mutations.


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