CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies.

2.50
Hdl Handle:
http://hdl.handle.net/10146/68873
Title:
CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies.
Authors:
Ogino, S.; Cantor, M.; Kawasaki, T.; Brahmandam, M.; Kirkner, G. J.; Weisenberger, D. J.; Campan, M.; Laird, P. W.; Loda, M.; Fuchs, C. S.
Abstract:
BACKGROUND: 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.
Citation:
Gut 2006, 55 (7):1000-1006
Journal:
Gut
Issue Date:
Jul-2006
URI:
http://hdl.handle.net/10146/68873
DOI:
10.1136/gut.2005.082933
PubMed ID:
16407376
Additional Links:
http://gut.bmj.com/cgi/content/full/55/7/1000; http://gut.bmj.com/content/vol55/issue7/
Type:
Article
Language:
en
Description:
KEYWORDS - 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.
ISSN:
0017-5749
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
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.en
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

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