title: Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence.
abstract: OBJECTIVE
  Epigenetic silencing of the DNA mismatch repair genes has been poorly described in colorectal carcinomas showing the classic adenoma-carcinoma pathway of carcinogenesis. The aim of this study was to investigate the methylation status of MutL homolog 1 (hMLH1), MutS homolog 2 (hMSH2), and O-6-methylguanine-DNA methyltransferase (MGMT) in a series of colorectal carcinomas that contain both adenomas and carcinomas.
  
  
  METHODS
  Promoter methylation of hMLH1, hMSH2, and MGMT was evaluated in normal mucosa, adenoma, and carcinoma samples from 112 colorectal cancer patients. Methylation was assessed by bisulfite modification and methylation-specific PCR. Expression of the gene products was also examined by immunohistochemistry.
  
  
  RESULTS
  Of the 112 adenomas, methylation was detected for hMLH1 (2, 1.8%), hMSH2 (9, 8.0%), and MGMT (38, 33.9%). In the carcinoma samples, methylation was seen in hMLH1 (2, 1.8%), hMSH2 (15, 13.4%), and MGMT (53, 47.3%). In normal mucosa, hMSH2 (6, 5.4%) and MGMT (12, 10.7%) were methylated, whereas hMLH1 was not. Immunohistochemical analysis revealed abnormal hMLH1 (14, 12.5%), hMSH2 (11, 9.8%), and MGMT (53, 47.3%) expression with a significant correlation between aberrant MGMT methylation and a loss of MGMT expression.
  
  
  CONCLUSIONS
  These data suggest that CpG island methylation in hMSH2 and MGMT, but not hMLH1, is closely related to carcinogenesis in colorectal carcinomas presenting with a conventional adenoma-carcinoma sequence. Therefore, the detection of hMSH2 and MGMT methylation may have clinical significance in the evaluation of colon cancer patients and in tumor-specific management of the disease.
authors.affiliation: Department of Pathology, Chonnam National University Medical School, 8, Hak-dong, Dong-gu, Gwangju 501-757, South Korea.
authors.forename: Kyung-Hwa
authors.initials: KH
authors.lastname: Lee
authors.forename: Ji-Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Nam
authors.forename: Chan
authors.initials: C
authors.lastname: Choi
authors.forename: Min-Cheol
authors.initials: MC
authors.lastname: Lee
authors.forename: Chang-Soo
authors.initials: CS
authors.lastname: Park
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Juhng
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D016001:Confidence Intervals; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D016208:Databases, Factual; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D016017:Odds Ratio; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes