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

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TitleEpigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma
AuthorsSuehiro, Y1 4
Wong, CW2
Chirieac, LR1
Kondo, Y6
Shen, L6
Renee Webb, C1
Chan, Y2
Chan, ASY2
Chan, TL2
Wu, TT1
Rashid, A1
Hamanaka, Y5
Hinoda, Y5
Shannon, RL4
Wang, X3
Morris, J3
Issa, JPJ6
Yuen, ST2
Leung, SY2
Hamilton, SR1 3
Issue Date2008
PublisherAmerican Association for Cancer Research.
CitationClinical Cancer Research, 2008, v. 14 n. 9, p. 2560-2569 [How to Cite?]
DOI: http://dx.doi.org/10.1158/1078-0432.CCR-07-1802
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.
ISSN1078-0432
2011 Impact Factor: 7.742
2011 SCImago Journal Rankings: 1.066
DOIhttp://dx.doi.org/10.1158/1078-0432.CCR-07-1802
ISI Accession Number IDWOS:000255616300006
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorSuehiro, Y
dc.contributor.authorWong, CW
dc.contributor.authorChirieac, LR
dc.contributor.authorKondo, Y
dc.contributor.authorShen, L
dc.contributor.authorRenee Webb, C
dc.contributor.authorChan, Y
dc.contributor.authorChan, ASY
dc.contributor.authorChan, TL
dc.contributor.authorWu, TT
dc.contributor.authorRashid, A
dc.contributor.authorHamanaka, Y
dc.contributor.authorHinoda, Y
dc.contributor.authorShannon, RL
dc.contributor.authorWang, X
dc.contributor.authorMorris, J
dc.contributor.authorIssa, JPJ
dc.contributor.authorYuen, ST
dc.contributor.authorLeung, SY
dc.contributor.authorHamilton, SR
dc.date.accessioned2010-09-06T09:41:27Z
dc.date.available2010-09-06T09:41:27Z
dc.date.issued2008
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.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationClinical Cancer Research, 2008, v. 14 n. 9, p. 2560-2569 [How to Cite?]
DOI: http://dx.doi.org/10.1158/1078-0432.CCR-07-1802
dc.identifier.citeulike5107029
dc.identifier.doihttp://dx.doi.org/10.1158/1078-0432.CCR-07-1802
dc.identifier.epage2569
dc.identifier.hkuros143514
dc.identifier.isiWOS:000255616300006
dc.identifier.issn1078-0432
2011 Impact Factor: 7.742
2011 SCImago Journal Rankings: 1.066
dc.identifier.issue9
dc.identifier.openurl
dc.identifier.pmid18451217
dc.identifier.scopuseid_2-s2.0-52049085300
dc.identifier.spage2560
dc.identifier.urihttp://hdl.handle.net/10722/88292
dc.identifier.volume14
dc.languageeng
dc.publisherAmerican Association for Cancer Research.
dc.publisher.placeUnited States
dc.relation.ispartofClinical Cancer Research
dc.relation.referencesReferences in Scopus
dc.subject.meshAdaptor Proteins, Signal Transducing - genetics - metabolism
dc.subject.meshColorectal Neoplasms - genetics - metabolism
dc.subject.meshCpG Islands - genetics
dc.subject.meshDNA Methylation
dc.subject.meshDNA Modification Methylases - genetics - metabolism
dc.subject.meshDNA Repair Enzymes - genetics - metabolism
dc.subject.meshEpigenesis, Genetic
dc.subject.meshFemale
dc.subject.meshGenes, APC
dc.subject.meshGenes, p53
dc.subject.meshGenes, ras
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshMutation
dc.subject.meshNuclear Proteins - genetics - metabolism
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshProto-Oncogene Proteins - genetics - metabolism
dc.subject.meshProto-Oncogene Proteins B-raf - genetics - metabolism
dc.subject.meshTumor Suppressor Proteins - genetics - metabolism
dc.subject.meshWnt Proteins - genetics - metabolism
dc.subject.meshras Proteins - genetics - metabolism
dc.titleEpigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma
dc.typeArticle
Author Affiliations
  1. Division of Pathology and Laboratory Medicine
  2. The University of Hong Kong
  3. University of Texas M. D. Anderson Cancer Center
  4. St. Luke's Episcopal Hospital Houston
  5. Yamaguchi University School of Medicine
  6. Division of Cancer Medicine