TY - JOUR
T1 - Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma
AU - Suehiro, Yutaka
AU - Wong, Chi Wai
AU - Chirieac, Lucian R.
AU - Kondo, Yutaka
AU - Shen, Lanlan
AU - Renee Webb, C.
AU - Chan, Yeewai
AU - Chan, Annie S.Y.
AU - Chan, Tsun Leung
AU - Wu, Tsung Teh
AU - Rashid, Asif
AU - Hamanaka, Yuichiro
AU - Hinoda, Yuji
AU - Shannon, Rhonda L.
AU - Wang, Xuemei
AU - Morris, Jeffrey
AU - Issa, Jean Pierre J.
AU - Yuen, Siu Tsan
AU - Leung, Suet Yi
AU - Hamilton, Stanley R.
PY - 2008/5/1
Y1 - 2008/5/1
N2 - 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→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.
AB - 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→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.
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U2 - 10.1158/1078-0432.CCR-07-1802
DO - 10.1158/1078-0432.CCR-07-1802
M3 - Article
C2 - 18451217
AN - SCOPUS:52049085300
SN - 1078-0432
VL - 14
SP - 2560
EP - 2569
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -