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

Yutaka Suehiro, Chi Wai Wong, Lucian R. Chirieac, Yutaka Kondo, Lanlan Shen, C. Renee Webb, Yeewai Chan, Annie S Y Chan, Tsun Leung Chan, Tsung Teh Wu, Asif Rashid, Yuichiro Hamanaka, Yuji Hinoda, Rhonda L. Shannon, Xuemei Wang, Jeffrey Morris, Jean Pierre J Issa, Siu Tsan Yuen, Suet Yi Leung, Stanley R. Hamilton

Research output: Contribution to journalArticle

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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→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.

Original languageEnglish (US)
Pages (from-to)2560-2569
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number9
DOIs
StatePublished - May 1 2008

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Adenomatous Polyposis Coli
Methyltransferases
Epigenomics
Colorectal Neoplasms
CpG Islands
Mutation
DNA
Phenotype
Odds Ratio
Methylation
APC Genes
Genes
Thymine
Cytosine
Guanine
Adenine
Multigene Family
Neoplasms
Carcinogenesis
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Suehiro, Y., Wong, C. W., Chirieac, L. R., Kondo, Y., Shen, L., Renee Webb, C., ... Hamilton, S. R. (2008). Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma. Clinical Cancer Research, 14(9), 2560-2569. https://doi.org/10.1158/1078-0432.CCR-07-1802

Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma. / Suehiro, Yutaka; Wong, Chi Wai; Chirieac, Lucian R.; Kondo, Yutaka; Shen, Lanlan; Renee Webb, C.; Chan, Yeewai; Chan, Annie S Y; Chan, Tsun Leung; Wu, Tsung Teh; Rashid, Asif; Hamanaka, Yuichiro; Hinoda, Yuji; Shannon, Rhonda L.; Wang, Xuemei; Morris, Jeffrey; Issa, Jean Pierre J; Yuen, Siu Tsan; Leung, Suet Yi; Hamilton, Stanley R.

In: Clinical Cancer Research, Vol. 14, No. 9, 01.05.2008, p. 2560-2569.

Research output: Contribution to journalArticle

Suehiro, Y, Wong, CW, Chirieac, LR, Kondo, Y, Shen, L, Renee Webb, C, Chan, Y, Chan, ASY, Chan, TL, Wu, TT, Rashid, A, Hamanaka, Y, Hinoda, Y, Shannon, RL, Wang, X, Morris, J, Issa, JPJ, Yuen, ST, Leung, SY & Hamilton, SR 2008, 'Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma', Clinical Cancer Research, vol. 14, no. 9, pp. 2560-2569. https://doi.org/10.1158/1078-0432.CCR-07-1802
Suehiro, Yutaka ; Wong, Chi Wai ; Chirieac, Lucian R. ; Kondo, Yutaka ; Shen, Lanlan ; Renee Webb, C. ; Chan, Yeewai ; Chan, Annie S Y ; Chan, Tsun Leung ; Wu, Tsung Teh ; Rashid, Asif ; Hamanaka, Yuichiro ; Hinoda, Yuji ; Shannon, Rhonda L. ; Wang, Xuemei ; Morris, Jeffrey ; Issa, Jean Pierre J ; Yuen, Siu Tsan ; Leung, Suet Yi ; Hamilton, Stanley R. / Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 9. pp. 2560-2569.
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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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