title: CHFR promoter hypermethylation in colon cancer correlates with the microsatellite instability phenotype.
abstract: A subset of sporadic colon cancers has been shown to have microsatellite instability caused by an epigenetic inactivation of the MLH1 gene by hypermethylation of the 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 the 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 HCT-116, DLD-1, RKO and HT29. Among the 61 primary colon cancer samples studied, hypermethylation of the MLH1 and the CHFR promoter was found in 31% of the tumors. In 68% of all primary cancers (13/19) with MLH1 promoter hypermethylation, hypermethylation of the CHFR promoter was observed as well (P-value < 0.0001, 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% (28/58), 40% (26/64), 21% (14/64), 50% (31/62), 43% (26/60) and 56% (35/63), 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.
authors.affiliation: Cancer Biology Program, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
authors.forename: Johann C
authors.initials: JC
authors.lastname: Brandes
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
authors.forename: Kim A D
authors.initials: KA
authors.lastname: Wouters
authors.forename: Matty P
authors.initials: MP
authors.lastname: Weijenberg
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D000070957:MutL Protein Homolog 1