Carcinogenesis Advance Access published online on March 10, 2005
Carcinogenesis, doi:10.1093/carcin/bgi058
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1 Cancer Biology Program, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
* To whom correspondence should be addressed. A subset of sporadic colon cancers has been shown to have microsatellite instability caused by epigenetic inactivation of the MLH1 gene by hypermethylation of the CpG island in its promoter region. We report here that in colorectal cancer, inactivation of the MLH1 gene is frequently accompanied by hypermethylation of CpG island in the promoter of the mitotic gene checkpoint with forkhead and ring finger domains (CHFR). This was first observed in the colon cancer cell lines HCT116, DLD1, RKO and HT29. Among 61 primary colon cancer samples studied, hypermethylation of the MLH1 promoter was found in 31% of the tumors while 30% had a hypermethylated CHFR promoter. In 73 % of all primary cancers (14/19) with hMLH-1 promoter hypermethylation, hypermethylation of the CHFR promoter was observed as well. (P-value 0.0003 Fisher's two sided exact). Hypermethylation of the HLTF, MGMT, RASSF1, APC, p14 and p16 promoter regions were also frequent events, being observed in 48 % (28/57), 42% (27/64), 21% (14/64), 50% (31/62), 43% (26/61) and 55% (35/64) respectively. However, methylation of these genes was not associated with methylation of either MLH1 or CHFR. The observed methylation profile was unrelated to Duke's stage. The coordinated loss of both mismatch repair caused by methylation of MLH1 and loss of checkpoint control associated with methylation of CHFR suggests the potential to overcome cell cycle checkpoints which may lead to an accumulation of mutations.
Received January 17, 2005
Revised February 16, 2005
Accepted February 16, 2005
CARCINOGENESIS
CHFR promoter hypermethylation in colon cancer correlates with the microsatellite instability phenotype
2 Department of Pathology, University Maastricht, 6200 MD Maastricht, The Netherlands
3 Department of Epidemiology, University Maastricht, 6200 MD Maastricht, The Netherlands
James G. Herman, E-mail: hermaji{at}jhmi.edu
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