Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma.
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.
Suehiro
Yutaka
Y
Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Wong
Chi Wai
CW
Chirieac
Lucian R
LR
Kondo
Yutaka
Y
Shen
Lanlan
L
Webb
C Renee
CR
Chan
Yee Wai
YW
Chan
Annie S Y
AS
Chan
Tsun Leung
TL
Wu
Tsung-Teh
TT
Rashid
Asif
A
Hamanaka
Yuichiro
Y
Hinoda
Yuji
Y
Shannon
Rhonda L
RL
Wang
Xuemei
X
Morris
Jeffrey
J
Issa
Jean-Pierre J
JP
Yuen
Siu Tsan
ST
Leung
Suet Yi
SY
Hamilton
Stanley R
SR
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
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