title: hMLH1 promoter hypermethylation and MSI status in human endometrial carcinomas with and without metastases.
abstract: We investigated the methylation status of mismatch repair gene hMLH1 in 80 primary human endometrial carcinomas (ECs) and in 30 metastatic lesions. It was correlated to the expression of hMLH1 protein, microsatellite instability (MSI) of ECs and to the well-known clinico-pathological variables of cancer. The hMLH1 promoter methylation was detected in 24 out of 64 (37.5 %) primary ECs but only in one out of 18 (5.6 %) metastatic lesions investigated. Promoter hMLH1 hypermethylation was found more often in early stage ECs and was associated with a decrease of hMLH1 protein expression immunohistochemically. An inverse relationship between hMLH1 expression and clinical stage of the disease was found (p = 0.048). Interestingly, there was a significant correlation between MSI and hMLH1 protein expression level (p = 0.042). MSI phenotype was found more often in EC metastases compared to the primary tumors (66.7 % vs 29.3 %; p = 0.039). However, neither hMLH1 promoter hypermethylation nor MSI was independent predictive factors for patient's outcome. Using an in vitro model we showed that hMLH1 methylation is reversible. These data showed that hMLH1 methylation with a consequent protein decrease occurred early during EC tumorigenesis and may cause a MSI phenotype, which occurs relatively late. MSI may be an important mechanism supporting further the tumor progression. These findings may have importance for the specific chemosensitization of the primary tumors/metastases and can improve our understanding of endometrial carcinogenesis in humans.
authors.affiliation: Department of Gynecology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Bischoff
authors.forename: A
authors.initials: A
authors.lastname: Ignatov
authors.forename: A
authors.initials: A
authors.lastname: Semczuk
authors.forename: C
authors.initials: C
authors.lastname: Schwarzenau
authors.forename: T
authors.initials: T
authors.lastname: Ignatov
authors.forename: T
authors.initials: T
authors.lastname: Krebs
authors.forename: D
authors.initials: D
authors.lastname: Küster
authors.forename: D
authors.initials: D
authors.lastname: Przadka-Rabaniuk
authors.forename: A
authors.initials: A
authors.lastname: Roessner
authors.forename: S D
authors.initials: SD
authors.lastname: Costa
authors.forename: R
authors.initials: R
authors.lastname: Schneider-Stock
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes; D001374:Azacitidine