title: Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma.
abstract: OBJECTIVE
  Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the O(6)-methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16/CDKN2A 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 hMLH1 leads to high levels of microsatellite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist.
  
  
  METHODS
  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.
authors.affiliation: Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suehiro
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Wong
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Lanlan
authors.initials: L
authors.lastname: Shen
authors.forename: C Renee
authors.initials: CR
authors.lastname: Webb
authors.forename: Yee Wai
authors.initials: YW
authors.lastname: Chan
authors.forename: Annie S Y
authors.initials: AS
authors.lastname: Chan
authors.forename: Tsun Leung
authors.initials: TL
authors.lastname: Chan
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hamanaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hinoda
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Shannon
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Morris
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.forename: Siu Tsan
authors.initials: ST
authors.lastname: Yuen
authors.forename: Suet Yi
authors.initials: SY
authors.lastname: Leung
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D017491:Genes, APC; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C117307:KRAS protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes