title: Microsatellite instability, MLH1 promoter methylation, and loss of mismatch repair in endometrial cancer and concomitant atypical hyperplasia.
abstract: OBJECTIVE
  MLH1 methylation is associated with the microsatellite instability (MSI) phenotype in endometrial cancer and atypical endometrial hyperplasia, a premalignant precursor to carcinoma. The observation that methylation is also seen in atypical endometrial hyperplasia without MSI suggests that methylation is an early event in endometrial tumorigenesis. Our objective was to determine if methylation is always present in MSI-positive atypical hyperplasia concomitant with MSI-positive, methylation-positive carcinoma.
  
  
  METHODS
  We used laser capture microdissection to study MLH1 methylation and MSI in a large series of endometrial cancer cases that had previously been shown to have methylation and the MSI-high (MSI-H) phenotype. We resampled areas of carcinoma from 27 patients along with 51 foci of concomitant atypical endometrial hyperplasia.
  
  
  RESULTS
  Consistent with previous reports, we saw MLH1 methylation in areas of atypical endometrial hyperplasia that did not show MSI. In addition, we noted that 18% of the MSI-H atypical endometrial hyperplasia DNAs lacked methylation of critical cytosines in the MLH1 promoter. Immunohistochemistry studies showed that these MSI-H unmethylated foci of atypical endometrial hyperplasia failed to express MLH1, as did regions of simple hyperplasia.
  
  
  CONCLUSIONS
  Methylation of the MLH1 promoter is an early event in endometrial tumorigenesis. Given that not all MSI-positive tissues had methylation at cytosines -229 and -231, it appears that methylation may not be required for MLH1 silencing and loss of mismatch repair.
authors.affiliation: Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: N
authors.initials: N
authors.lastname: Horowitz
authors.forename: K
authors.initials: K
authors.lastname: Pinto
authors.forename: D G
authors.initials: DG
authors.lastname: Mutch
authors.forename: T J
authors.initials: TJ
authors.lastname: Herzog
authors.forename: J S
authors.initials: JS
authors.lastname: Rader
authors.forename: R
authors.initials: R
authors.lastname: Gibb
authors.forename: T
authors.initials: T
authors.lastname: Bocker-Edmonston
authors.forename: P J
authors.initials: PJ
authors.lastname: Goodfellow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D019175:DNA Methylation; D004260:DNA Repair; D004714:Endometrial Hyperplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009687:Nuclear Proteins; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1