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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, Y5
Shen, L5
Renee Webb, C1
Chan, Y2
Chan, ASY2
Chan, TL2
Wu, TT1
Rashid, A1
Hamanaka, Y6
Hinoda, Y6
Shannon, RL4
Wang, X3
Morris, J3
Issa, JPJ5
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
2013 Impact Factor: 8.193
2013 SCImago Journal Rankings: 5.150
 
DOIhttp://dx.doi.org/10.1158/1078-0432.CCR-07-1802
 
ISI Accession Number IDWOS:000255616300006
 
ReferencesReferences in Scopus
 
DC FieldValue
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
2013 Impact Factor: 8.193
2013 SCImago Journal Rankings: 5.150
 
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
 
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<contributor.author>Kondo, Y</contributor.author>
<contributor.author>Shen, L</contributor.author>
<contributor.author>Renee Webb, C</contributor.author>
<contributor.author>Chan, Y</contributor.author>
<contributor.author>Chan, ASY</contributor.author>
<contributor.author>Chan, TL</contributor.author>
<contributor.author>Wu, TT</contributor.author>
<contributor.author>Rashid, A</contributor.author>
<contributor.author>Hamanaka, Y</contributor.author>
<contributor.author>Hinoda, Y</contributor.author>
<contributor.author>Shannon, RL</contributor.author>
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<description.abstract>Purpose: 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&#8594;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 &lt; 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 &lt; 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 &lt; 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P &lt; 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. &#169; 2008 American Association for Cancer Research.</description.abstract>
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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. Division of Cancer Medicine
  6. Yamaguchi University School of Medicine