Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients

Instability of microsatellite repeat sequences has been observed in colorec tal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal ca ncer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mi smatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been st udied primarily in sporadic tumours showing predominantly somatic hypermeth ylation of MLH1. The present study shows that all endometrial carcinomas (n = 12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI -high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in e ndometrial hyperplasias from MSN2 mutation carriers, in contrast to hyperpl asias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endome trial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical ana lysis of MLH1, MSH2, and MSH6 could predict the identified germline mutatio n. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR gene s is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the ape of onset o f carcinoma, suggesting differences in the rate of tumour progression. A hi gh frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR gems. Copyright (C) 2000 John W iley & Sons, Ltd.