MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer

The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant en dometrial samples from 3 patient groups: (1) 10 endometrial cancer patients from hereditary non-polyposis colorectal cancer (HNPCC) families with (n = 6) or without (n = 4) a known germline mutation; (11) 15 women from HNPCC families with (n = 7) or without (n = 8) a known germline mutation, who und erwent endometrial sampling for non-malignant reasons; (III) 38 endometrial cancer patients <50 years of age, without HNPCC family history. Immunostai ning for MLH1 and MSH2 was performed on paraffin-embedded sections. In grou p III, tumor DNA was examined for microsatellite instability (MSI) and MLH1 , MSH2 and MSH6 mutation analysis was carried out. In 6/6 MLH1/MSH2 mutatio n carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation. In 3 MLHI mutati on carriers. MLHI protein loss was also observed in concurrent endometrial hyperplasia, In group II, no protein loss was detected in normal endometria l tissue samples; in 3/4 patients with endometrial hyperplasia, MLH1/MSH2 p rotein loss was observed. In group Ill, protein loss was detected in 12/38 patients (9 MLH1, 3 MSH2), while in 3/11 patients with concurrent endometri al hyperplasia protein loss was also observed in the hyperplasia. MSI analy sis in group III revealed 26 MSI-low and IZ MSI-high tumors. Mutation analy sis in 28/38 patients showed only I missense MSH6 and no MLHI or MSH2 germl ine mutations, In group III, loss of MLH1/MSH2 protein expression was not r elated to the presence of MSI or MLH1/MSH2 germline mutations, In conclusio n, MLH1 or MSH2 protein loss in HNPCC-related endometrial neoplasia is stro ngly related to corresponding germline mutations. This relation was not cle arly present in young sporadic endometrial cancer patients. Immunohistochem ical pre-screening of the MLHI and MSHZ 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 earl y event in endometrial carcinogenesis. <(c)> 2001 Wiley-Liss. Inc.