Methylation of the hMLH1 and hMSH2 promoter in early-onset sporadic colorectal carcinomas with microsatellite instability.
OBJECTIVE
Microsatellite instability (MSI) occurring from defects in mismatch repair has been found to be associated with about 15% of sporadic colorectal carcinomas. This study examined the incidence of MSI in early-onset sporadic colorectal carcinomas and the role of methylation of the hMLH1 and hMSH2 promoter in sporadic colorectal carcinoma presenting with MSI.


METHODS
MSI in 38 early-onset and 40 late-onset sporadic colorectal carcinomas were determined as MSI-H, MSI-L, and MSS using five markers. Methylation of the promoter region in hMLH1 and hMSH2 was assessed using methylation-specific PCR (MSP). Their protein expressions were also identified on immunohistochemical staining.


RESULTS
MSI-H, MSI-L, and MSS were found in six (15.8%), three (7.9%), and 29 (76.3%) cases, respectively, in the early-onset group, and in one (2.5%), five (12.5%), and 34 (85%) cases in the late-onset group. Five cases (71.4%) of MSI-H and two cases (25%) of MSI-L showed methylation of the promoter region in hMLH1. No cases with methylation of the promoter region expressed the hMLH1 protein. Only one case of MSI-H showed methylation of the promoter region in hMSH2 with lack of expression of hMSH2.


CONCLUSIONS
The mutator pathway in colorectal carcinogenesis appeared more frequently in early-onset than in late-onset colorectal carcinoma. Many cases with MSI in sporadic colorectal carcinoma may be associated with methylation of the promoter in hMLH1.
Kim
Hee C
HC
Department of Surgery, University of Ulsan College of Medicine and Laboratory of Cancer Biology and Genetics, Asan Institute for Life Sciences, 388-1 Poongnap-Dong, Songpa-Ku, Seoul 138-736, Korea.
Kim
Chang N
CN
Yu
Chang S
CS
Roh
Seon A
SA
Kim
Jin C
JC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
D009363:Neoplasm Proteins