Microsatellite instability caused by hMLH1 promoter methylation increases with tumor progression in right-sided sporadic colorectal cancer.
OBJECTIVE
A subset of sporadic colorectal cancers (SCRCs) exhibits microsatellite instability (MSI). Most MSI in SCRCs is caused by hMLH1 inactivation due to promoter methylation. However, the role of MSI in the progression of SCRCs remains unclear.


METHODS
Thirty-two intramucosal cancers and 63 cancers with submucosal invasion were assigned to group 1 (early-stage cancer), and 30 Dukes' B and 26 Dukes' C cancers to group 2 (advanced-stage cancer). hMLH1 promoter methylation status was determined by methylation-specific PCR. MSI was determined using five markers. hMLH1 expression was determined immunohistochemically.


RESULTS
MSI was found in 1 of 95 (1.1%) tumors in group 1, compared with 4 of 56 (7.1%) tumors in group 2. In right-sided tumors, the overall frequency of hMLH1-methylation-positive tumors in group 1 was not significantly different from that in group 2 (17 of 43, 39.5%, vs. 9 of 23, 39.1%). In right-sided tumors with hMLH1 promoter methylation, the frequency of MSI-positive tumors in group 1 was significantly lower than that in group 2 (1 of 17, 5.9%, vs. 4 of 9, 44.4%, p=0.0081).


CONCLUSIONS
The frequency of MSI caused by hMLH1 promoter methylation increases with tumor progression in right-sided SCRCs.
Noda
Hiroshi
H
Department of Molecular Diagnosis, Japanese Foundation for Cancer Research, and Department of Surgery, Jichi Medical School, Tokyo Medical and Dental University, Tokyo, Japan.
Kato
Yo
Y
Yoshikawa
Hirohide
H
Arai
Masami
M
Togashi
Kazutomo
K
Nagai
Hideo
H
Konishi
Fumio
F
Miki
Yoshio
Y
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008745:Methylation; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1