MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer
Maran J.W. Berends
Department of Gastroenterology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorHarry Hollema
Department of Pathology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorYing Wu
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorTineke van der Sluis
Department of Pathology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorRob G.J. Mensink
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorKlaske A. ten Hoor
Department of Gynaecology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorRolf H. Sijmons
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorElisabeth G.E. de Vries
Department of Medical Oncology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorElisabeth Pras
Department of Radiotherapy, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorMarian J.E. Mourits
Department of Gynaecology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorRobert M.W. Hofstra
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorCharles H.C.M. Buys
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorJan H. Kleibeuker
Department of Gastroenterology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorCorresponding Author
Ate G.J. van der Zee
Department of Gynaecology, University Hospital Groningen, Groningen, The Netherlands
Fax: +31-50-3611806
Department of Gynaecology, University Hospital Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, the NetherlandsSearch for more papers by this authorMaran J.W. Berends
Department of Gastroenterology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorHarry Hollema
Department of Pathology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorYing Wu
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorTineke van der Sluis
Department of Pathology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorRob G.J. Mensink
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorKlaske A. ten Hoor
Department of Gynaecology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorRolf H. Sijmons
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorElisabeth G.E. de Vries
Department of Medical Oncology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorElisabeth Pras
Department of Radiotherapy, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorMarian J.E. Mourits
Department of Gynaecology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorRobert M.W. Hofstra
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorCharles H.C.M. Buys
Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorJan H. Kleibeuker
Department of Gastroenterology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorCorresponding Author
Ate G.J. van der Zee
Department of Gynaecology, University Hospital Groningen, Groningen, The Netherlands
Fax: +31-50-3611806
Department of Gynaecology, University Hospital Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, the NetherlandsSearch for more papers by this authorAbstract
The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant endometrial samples from 3 patient groups: (I) 10 endometrial cancer patients from hereditary non-polyposis colorectal cancer (HNPCC) families with (n = 6) or without (n = 4) a known germline mutation; (II) 15 women from HNPCC families with (n = 7) or without (n = 8) a known germline mutation, who underwent endometrial sampling for non-malignant reasons; (III) 38 endometrial cancer patients <50 years of age, without HNPCC family history. Immunostaining for MLH1 and MSH2 was performed on paraffin-embedded sections. In group III, tumor DNA was examined for microsatellite instability (MSI) and MLH1, MSH2 and MSH6 mutation analysis was carried out. In 6/6 MLH1/MSH2 mutation carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation. In 3 MLH1 mutation carriers, MLH1 protein loss was also observed in concurrent endometrial hyperplasia. In group II, no protein loss was detected in normal endometrial tissue samples; in 3/4 patients with endometrial hyperplasia, MLH1/MSH2 protein loss was observed. In group III, protein loss was detected in 12/38 patients (9 MLH1, 3 MSH2), while in 3/11 patients with concurrent endometrial hyperplasia protein loss was also observed in the hyperplasia. MSI analysis in group III revealed 26 MSI-low and 12 MSI-high tumors. Mutation analysis in 28/38 patients showed only 1 missense MSH6 and no MLH1 or MSH2 germline mutations. In group III, loss of MLH1/MSH2 protein expression was not related to the presence of MSI or MLH1/MSH2 germline mutations. In conclusion, MLH1 or MSH2 protein loss in HNPCC-related endometrial neoplasia is strongly related to corresponding germline mutations. This relation was not clearly present in young sporadic endometrial cancer patients. Immunohistochemical pre-screening of the MLH1 and MSH2 proteins in endometrial hyperplasia or cancer can thus be helpful in HNPCC families. Frequent loss of MLH1 or MSH2 protein in endometrial hyperplasia indicates that this loss is an early event in endometrial carcinogenesis. © 2001 Wiley-Liss, Inc.
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