title: APC gene methylation is inversely correlated with features of the CpG island methylator phenotype in colorectal cancer.
abstract: The notion of a CpG island methylator phenotype (CIMP) was proposed to describe a subset of colorectal cancers (CRC) displaying frequent and concordant methylation of CpG islands located within gene promoter regions. Some workers have failed to observe associations between CIMP and specific clinicopathological features of CRC, possibly because of the choice of genes used to define this phenotype. The aim of the current study was to determine whether the aberrant methylation of 6 genes implicated in CRC development was associated with the same phenotypic features of this tumour type. The MethyLight assay was used to provide quantitative estimates of MLH1, P16, TIMP3, P14, DAPK and APC methylation levels in 199 unselected colorectal tumours. The methylation of MLH1, P16, TIMP3 and P14 was highly concordant (p < 0.0001 for each pair) but that of DAPK and APC was not. An inverse association was observed between the methylation of APC and TIMP3 (p = 0.004). Methylation of the MLH1, P16, TIMP3 and P14 genes was associated with tumour infiltrating lymphocytes (p < 0.05), microsatellite instability (p < 0.001), BRAF mutation (p < 0.0001) and elevated concentrations of the methyl group carriers tetrahydrofolate (THF) and 5,10-methylene THF (p < 0.05). In contrast, APC methylation was associated with wildtype BRAF (p = 0.003) and with lower concentrations of methyl group carriers (p < 0.05). These findings highlight the importance of gene selection in studies that aim to characterize the biological features and clinical behaviour of CIMP+ tumours.
authors.affiliation: School of Surgery and Pathology, University of Western Australia, Nedlands, Australia. barry.iacopetta@uwa.edu.au
authors.forename: Barry
authors.initials: B
authors.lastname: Iacopetta
authors.forename: Fabienne
authors.initials: F
authors.lastname: Grieu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Andrew
authors.initials: A
authors.lastname: Ruszkiewicz
authors.forename: Maria
authors.initials: M
authors.lastname: Caruso
authors.forename: James
authors.initials: J
authors.lastname: Moore
authors.forename: Goh
authors.initials: G
authors.lastname: Watanabe
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D017491:Genes, APC; D019942:Genes, p16; D006801:Humans; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C117307:KRAS protein, human; C426009:LAMTOR2 protein, mouse; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C088390:TIMP3 protein, human; C495901:TP53 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins