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Article: Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma

TitleEpigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma
Authors
Issue Date2008
PublisherAmerican Association for Cancer Research.
Citation
Clinical Cancer Research, 2008, v. 14 n. 9, p. 2560-2569 How to Cite?
AbstractPurpose: Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the 06-methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16ICDKN2A genes. Epigenetic alterations affect genetic events: Loss of MGMT via hypermethylation reportedly predisposes to guanine-to-adenine or cytosine-to-thymine (G:C→A:T) transition mutations in KRAS and P53, and silencing of hMLHI leads to high levels of microsatel-lite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist. Experimental Design: We evaluated the relationships of aberrant methylation of APC, MGMT, hMLH1 P16, N33, and five MINTs to mutations in APC, KRAS, BRAF, and P53 in 208 colorectal carcinomas. Results: We found that APC hypermethylation was age related (P = 0.04), in contrast to the other genes, and did not cluster with CpG island methylator phenotype (CIMP) markers. Hypermethylation of APC concurrently with either MGMT or hMLH1 was strongly associated with occurrence of G-to-A transitions in APC [odds ratio (OR), 26.8; P < 0.0002 from multivariable logic regression model], but C-to-T transitions had no associations. There was no relationship of hypermethylation of any gene, including MGMT, with G-to-A or C-to-T transitions in KRAS or P53, although APC hypermethylation was associated with P53 mutation (P < 0.0002). CIMP with MSI-H due to hMLH1 hypermethylation, or CIMP with loss of MGMT expression in non-MSI-H tumors, was associated with BRAF mutation (OR, 4.5; P < 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P < 0.0002). Conclusions: Our findings suggest that the heterogeneous epigenetic dysregulation of promoter methylation in various genes is interrelated with the occurrence of mutations, as manifested in epigenetic-genetic subgroups of tumors. © 2008 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/88292
ISSN
2014 Impact Factor: 8.722
2014 SCImago Journal Rankings: 4.097
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorSuehiro, Yen_HK
dc.contributor.authorWong, CWen_HK
dc.contributor.authorChirieac, LRen_HK
dc.contributor.authorKondo, Yen_HK
dc.contributor.authorShen, Len_HK
dc.contributor.authorRenee Webb, Cen_HK
dc.contributor.authorChan, Yen_HK
dc.contributor.authorChan, ASYen_HK
dc.contributor.authorChan, TLen_HK
dc.contributor.authorWu, TTen_HK
dc.contributor.authorRashid, Aen_HK
dc.contributor.authorHamanaka, Yen_HK
dc.contributor.authorHinoda, Yen_HK
dc.contributor.authorShannon, RLen_HK
dc.contributor.authorWang, Xen_HK
dc.contributor.authorMorris, Jen_HK
dc.contributor.authorIssa, JPJen_HK
dc.contributor.authorYuen, STen_HK
dc.contributor.authorLeung, SYen_HK
dc.contributor.authorHamilton, SRen_HK
dc.date.accessioned2010-09-06T09:41:27Z-
dc.date.available2010-09-06T09:41:27Z-
dc.date.issued2008en_HK
dc.identifier.citationClinical Cancer Research, 2008, v. 14 n. 9, p. 2560-2569en_HK
dc.identifier.issn1078-0432en_HK
dc.identifier.urihttp://hdl.handle.net/10722/88292-
dc.description.abstractPurpose: Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the 06-methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16ICDKN2A genes. Epigenetic alterations affect genetic events: Loss of MGMT via hypermethylation reportedly predisposes to guanine-to-adenine or cytosine-to-thymine (G:C→A:T) transition mutations in KRAS and P53, and silencing of hMLHI leads to high levels of microsatel-lite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist. Experimental Design: We evaluated the relationships of aberrant methylation of APC, MGMT, hMLH1 P16, N33, and five MINTs to mutations in APC, KRAS, BRAF, and P53 in 208 colorectal carcinomas. Results: We found that APC hypermethylation was age related (P = 0.04), in contrast to the other genes, and did not cluster with CpG island methylator phenotype (CIMP) markers. Hypermethylation of APC concurrently with either MGMT or hMLH1 was strongly associated with occurrence of G-to-A transitions in APC [odds ratio (OR), 26.8; P < 0.0002 from multivariable logic regression model], but C-to-T transitions had no associations. There was no relationship of hypermethylation of any gene, including MGMT, with G-to-A or C-to-T transitions in KRAS or P53, although APC hypermethylation was associated with P53 mutation (P < 0.0002). CIMP with MSI-H due to hMLH1 hypermethylation, or CIMP with loss of MGMT expression in non-MSI-H tumors, was associated with BRAF mutation (OR, 4.5; P < 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P < 0.0002). Conclusions: Our findings suggest that the heterogeneous epigenetic dysregulation of promoter methylation in various genes is interrelated with the occurrence of mutations, as manifested in epigenetic-genetic subgroups of tumors. © 2008 American Association for Cancer Research.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research.en_HK
dc.relation.ispartofClinical Cancer Researchen_HK
dc.subject.meshAdaptor Proteins, Signal Transducing - genetics - metabolismen_HK
dc.subject.meshColorectal Neoplasms - genetics - metabolismen_HK
dc.subject.meshCpG Islands - geneticsen_HK
dc.subject.meshDNA Methylationen_HK
dc.subject.meshDNA Modification Methylases - genetics - metabolismen_HK
dc.subject.meshDNA Repair Enzymes - genetics - metabolismen_HK
dc.subject.meshEpigenesis, Geneticen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshGenes, APCen_HK
dc.subject.meshGenes, p53en_HK
dc.subject.meshGenes, rasen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiddle Ageden_HK
dc.subject.meshMutationen_HK
dc.subject.meshNuclear Proteins - genetics - metabolismen_HK
dc.subject.meshPromoter Regions, Geneticen_HK
dc.subject.meshProto-Oncogene Proteins - genetics - metabolismen_HK
dc.subject.meshProto-Oncogene Proteins B-raf - genetics - metabolismen_HK
dc.subject.meshTumor Suppressor Proteins - genetics - metabolismen_HK
dc.subject.meshWnt Proteins - genetics - metabolismen_HK
dc.subject.meshras Proteins - genetics - metabolismen_HK
dc.titleEpigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1078-0432&volume=14&issue=9&spage=2560&epage=9&date=2008&atitle=Epigenetic-Genetic+Interactions+in+the+APC/WNT,+RAS/RAF,+and+P53+Pathways+in+Colorectal+Carcinomaen_HK
dc.identifier.emailChan, TL:tlchan@hku.hken_HK
dc.identifier.emailLeung, SY:suetyi@hkucc.hku.hken_HK
dc.identifier.authorityChan, TL=rp00418en_HK
dc.identifier.authorityLeung, SY=rp00359en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-07-1802en_HK
dc.identifier.pmid18451217en_HK
dc.identifier.scopuseid_2-s2.0-52049085300en_HK
dc.identifier.hkuros143514en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-52049085300&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume14en_HK
dc.identifier.issue9en_HK
dc.identifier.spage2560en_HK
dc.identifier.epage2569en_HK
dc.identifier.isiWOS:000255616300006-
dc.publisher.placeUnited Statesen_HK
dc.identifier.citeulike5107029-

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