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dc.contributor.authorOgino, S.
dc.contributor.authorCantor, M.
dc.contributor.authorKawasaki, T.
dc.contributor.authorBrahmandam, M.
dc.contributor.authorKirkner, G. J.
dc.contributor.authorWeisenberger, D. J.
dc.contributor.authorCampan, M.
dc.contributor.authorLaird, P. W.
dc.contributor.authorLoda, M.
dc.contributor.authorFuchs, C. S.
dc.date.accessioned2009-05-25T07:42:43Z
dc.date.available2009-05-25T07:42:43Z
dc.date.issued2006-07
dc.identifier.citationGut 2006, 55 (7):1000-1006en
dc.identifier.issn0017-5749
dc.identifier.pmid16407376
dc.identifier.doi10.1136/gut.2005.082933
dc.identifier.urihttp://hdl.handle.net/10146/68873
dc.descriptionKEYWORDS - CLASSIFICATION: analysis;biomarkers of exposure & effect: validation;Boston;Colorectal Neoplasms;CpG Islands;DNA Methylation;genetics;Genetic Markers;Genetic Predisposition to Disease;Health Surveys;Humans;Microsatellite Repeats;Prospective Studies;Proteins;Proto-Oncogene Proteins;Proto-Oncogene Proteins B-raf;Research;Reverse Transcriptase Polymerase Chain Reaction.en
dc.description.abstractBACKGROUND: The concept of CpG island methylator phenotype (CIMP) is not universally accepted. Even if specific clinicopathological features have been associated with CIMP, investigators often failed to demonstrate a bimodal distribution of the number of methylated markers, which would suggest CIMP as a distinct subtype of colorectal cancer. Previous studies primarily used methylation specific polymerase chain reaction which might detect biologically insignificant low levels of methylation. AIM: To demonstrate a distinct genetic profile of CIMP colorectal cancer using quantitative DNA methylation analysis that can distinguish high from low levels of DNA methylation. MATERIALS AND METHODS: We developed quantitative real time polymerase chain reaction (MethyLight) assays and measured DNA methylation (percentage of methylated reference) of five carefully selected loci (promoters of CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 460 colorectal cancers from large prospective cohorts. RESULTS: There was a clear bimodal distribution of 80 microsatellite instability-high (MSI-H) tumours according to the number of methylated promoters, with no tumours showing 3/5 methylated loci. Thus we defined CIMP as having >or=4/5 methylated loci, and 17% (78) of the 460 tumours were classified as CIMP. CIMP was significantly associated with female sex, MSI, BRAF mutations, and wild-type KRAS. Both CIMP MSI-H tumours and CIMP microsatellite stable (MSS) tumours showed much higher frequencies of BRAF mutations (63% and 54%) than non-CIMP counterparts (non-CIMP MSI-H (0%, p<10(-5)) and non-CIMP MSS tumours (6.6%, p<10(-4)), respectively). CONCLUSION: CIMP is best characterised by quantitative DNA methylation analysis. CIMP is a distinct epigenotype of colorectal cancer and may be less frequent than previously reported.
dc.language.isoenen
dc.relation.urlhttp://gut.bmj.com/cgi/content/full/55/7/1000en
dc.relation.urlhttp://gut.bmj.com/content/vol55/issue7/en
dc.subject.meshColorectal Neoplasms
dc.subject.meshCpG Islands
dc.subject.meshDNA Methylation
dc.subject.meshGenetic Markers
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshHealth Surveys
dc.subject.meshHumans
dc.subject.meshMicrosatellite Repeats
dc.subject.meshProspective Studies
dc.subject.meshProto-Oncogene Proteins
dc.subject.meshProto-Oncogene Proteins B-raf
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction
dc.subject.meshras Proteins
dc.titleCpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies.en
dc.typeArticleen
dc.identifier.journalGuten
html.description.abstractBACKGROUND: The concept of CpG island methylator phenotype (CIMP) is not universally accepted. Even if specific clinicopathological features have been associated with CIMP, investigators often failed to demonstrate a bimodal distribution of the number of methylated markers, which would suggest CIMP as a distinct subtype of colorectal cancer. Previous studies primarily used methylation specific polymerase chain reaction which might detect biologically insignificant low levels of methylation. AIM: To demonstrate a distinct genetic profile of CIMP colorectal cancer using quantitative DNA methylation analysis that can distinguish high from low levels of DNA methylation. MATERIALS AND METHODS: We developed quantitative real time polymerase chain reaction (MethyLight) assays and measured DNA methylation (percentage of methylated reference) of five carefully selected loci (promoters of CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 460 colorectal cancers from large prospective cohorts. RESULTS: There was a clear bimodal distribution of 80 microsatellite instability-high (MSI-H) tumours according to the number of methylated promoters, with no tumours showing 3/5 methylated loci. Thus we defined CIMP as having >or=4/5 methylated loci, and 17% (78) of the 460 tumours were classified as CIMP. CIMP was significantly associated with female sex, MSI, BRAF mutations, and wild-type KRAS. Both CIMP MSI-H tumours and CIMP microsatellite stable (MSS) tumours showed much higher frequencies of BRAF mutations (63% and 54%) than non-CIMP counterparts (non-CIMP MSI-H (0%, p<10(-5)) and non-CIMP MSS tumours (6.6%, p<10(-4)), respectively). CONCLUSION: CIMP is best characterised by quantitative DNA methylation analysis. CIMP is a distinct epigenotype of colorectal cancer and may be less frequent than previously reported.


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