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 colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation 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 endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high 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 genes.

de Leeuw WJ ，Dierssen J ，Vasen HF ，Wijnen JT ，Kenter GG ，Meijers-Heijboer H ，Brocker-Vriends A ，Stormorken A ，Moller P ，Menko F ，Cornelisse CJ ，Morreau H ... -  《JOURNAL OF PATHOLOGY》

Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes.

Mead LJ ，Jenkins MA ，Young J ，Royce SG ，Smith L ，St John DJ ，Macrae F ，Giles GG ，Hopper JL ，Southey MC ... -  《CLINICAL CANCER RESEARCH》

Molecular analysis of endometrial hyperplasia in HNPCC-suspicious patients may predict progression to endometrial carcinoma.

Sutter C ，Dallenbach-Hellweg G ，Schmidt D ，Baehring J ，Bielau S ，von Knebel Doeberitz M ，Gebert J ... -  《INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY》

High frequency of microsatellite instability and loss of mismatch-repair protein expression in patients with double primary tumors of the endometrium and colorectum.

Planck M ，Rambech E ，Möslein G ，Müller W ，Olsson H ，Nilbert M ... -  《CANCER》

Mononucleotide precedes dinucleotide repeat instability during colorectal tumour development in Lynch syndrome patients.

Ferreira AM ，Westers H ，Sousa S ，Wu Y ，Niessen RC ，Olderode-Berends M ，van der Sluis T ，Reuvekamp PT ，Seruca R ，Kleibeuker JH ，Hollema H ，Sijmons RH ，Hofstra RM ... -  《-》