title: Microsatellite instability, loss of heterozygosity, and loss of hMLH1 and hMSH2 protein expression in endometrial carcinoma.
abstract: Microsatellite instability (MSI) due to replication errors occurs frequently in hereditary tumors. Association with functional inactivation of the mismatch repair (MMR) genes and lack of protein expression has been described. In endometrial carcinoma (EC), the prevalence and clinical significance of these phenomena are not well known. Therefore, DNA samples from 89 EC and 5 metachronous tumors were analyzed with polymerase chain reaction, using 5 microsatellite markers and a DNA sequencer for amplicon detection. The results were correlated with immunohistochemistry of hMLH1 and hMSH2. MSI at >or=2 loci (MSI-H) was detected in 10/89 EC (11%); 1 of 10 showed loss of both hMLH1 and hMSH2, and 5 of 10 showed loss of hMLH1 (P < 0.0001). MSI-H was observed frequently in tumors with mucinous differentiation (P = 0.048), >10% of solid-cribriform pattern (P = 0.037), International Federation of Obstetrics and Gynecology (FIGO) stage III to IV (4 of 13; P = 0.016), and necrosis >5% (P = 0.07). Loss of heterozygosity (LOH) in >or=1 loci was found in 17 of 156 (11%). Survival (Kaplan-Meier) was longer for patients with endometrioid tumors with predominant glandular pattern, <5% necrosis, low FIGO stage and grade, superficial myometrial infiltration, no lymph-vascular invasion (LVI), and loss of hMLH1 expression (all P <or= 0.04). Cox analysis showed independent value for stage, grade, histologic type and pattern, LVI, and hMLH1 expression (all P < 0.05). Age, MSI status, LOH, peritumoral inflammatory reaction, hMSH2, and development of metachronous tumors did not influence survival. In conclusion, MSI phenotype was observed in a small subset of mainly advanced-stage EC, frequently showing mucinous differentiation, areas of solid-cribriform pattern, and necrosis. It is often associated with loss of hMLH1 expression, which may be a prognostic marker, but only rarely with defects of hMSH2.
authors.affiliation: Institute of Pathology and the Department of Clinical Chemistry, Grosshadern Hospital Ludwig-Maximilian University of Munich, Munich, Germany.
authors.forename: Gloria
authors.initials: G
authors.lastname: Peiró
authors.forename: Joachim
authors.initials: J
authors.lastname: Diebold
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.forename: Heike
authors.initials: H
authors.lastname: Ruebsamen
authors.forename: Pia
authors.initials: P
authors.lastname: Lohse
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.forename: Udo
authors.initials: U
authors.lastname: Löhrs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins; D004273:DNA, Neoplasm / Q000032:analysis; D004268:DNA-Binding Proteins; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein