Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis

Takeshi Nagasaka, Ajay Goel, Kenji Notohara, Takaomi Takahata, Hiromi Sasamoto, Takuyuki Uchida, Naoshi Nishida, Noriaki Tanaka, Clement Richard Boland, Nagahide Matsubara

Research output: Contribution to journalArticle

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Abstract

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair gene which is frequently methylated in colorectal cancer (CRC). However, it remains controversial whether methylation of specific CpG sequences within MGMT promoter leads to loss of its protein expression, and if MGMT methylation correlates with G to A transition mutations in KRAS. Two methylation sensitive regions (Mp and Eh region) of MGMT promoter were investigated in 593 specimens of colorectal tissue: 233 CRCs, 104 adenomatous polyps (AP), 220 normal colonic mucosa from CRC patients (N-C) and 36 normal colonic mucosa specimens obtained from subjects without colorectal neoplasia (N-N) by combined bisulfite restriction analysis (COBRA). The region-specific methylation data were compared to the MGMT protein expression, spectrum of KRAS mutations and other clinical features. Extensive (including both Mp and Eh) and partial (either Mp or Eh) MGMT methylation were found in 24.5% and 11.6% of CRCs, 3.8% and 27.9% of APs, 0.5% and 7.7% of C-Ns and 2.8% and 2.8% of N-Ns, respectively. Extensive methylation of MGMT promoter was primarily present in CRCs while partial methylation was common in APs. Extensive methylation of MGMT promoter was associated with loss/reduced protein expression (p <0.0001), as well as with G to A mutations in KRAS (p = 0.0017). We herein provide first evidence that extensive methylation of MGMT promoter region is essential for methylation-induced silencing of this gene. Our data suggest that MGMT methylation may evolve and spread throughout the promoter in a stepwise manner as the colonic epithelial cells progress through the classical-adenoma-cancer multistep cascade.

Original languageEnglish
Pages (from-to)2429-2436
Number of pages8
JournalInternational Journal of Cancer
Volume122
Issue number11
DOIs
Publication statusPublished - Jun 1 2008

Fingerprint

Methyltransferases
Methylation
Colon
Carcinogenesis
DNA Methylation
DNA
Genes
Mutation
Colorectal Neoplasms
Mucous Membrane
Protein Methyltransferases
Adenomatous Polyps
O-(6)-methylguanine
Gene Silencing
Genetic Promoter Regions
DNA Repair
Adenoma
Neoplasms
Proteins
Epithelial Cells

Keywords

  • Adenomatous polyps
  • Colorectal cancer
  • KRAS mutations
  • O-methylguanine-DNA methyltransferase
  • Promoter methylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Nagasaka, T., Goel, A., Notohara, K., Takahata, T., Sasamoto, H., Uchida, T., ... Matsubara, N. (2008). Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis. International Journal of Cancer, 122(11), 2429-2436. https://doi.org/10.1002/ijc.23398

Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis. / Nagasaka, Takeshi; Goel, Ajay; Notohara, Kenji; Takahata, Takaomi; Sasamoto, Hiromi; Uchida, Takuyuki; Nishida, Naoshi; Tanaka, Noriaki; Boland, Clement Richard; Matsubara, Nagahide.

In: International Journal of Cancer, Vol. 122, No. 11, 01.06.2008, p. 2429-2436.

Research output: Contribution to journalArticle

Nagasaka, T, Goel, A, Notohara, K, Takahata, T, Sasamoto, H, Uchida, T, Nishida, N, Tanaka, N, Boland, CR & Matsubara, N 2008, 'Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis', International Journal of Cancer, vol. 122, no. 11, pp. 2429-2436. https://doi.org/10.1002/ijc.23398
Nagasaka, Takeshi ; Goel, Ajay ; Notohara, Kenji ; Takahata, Takaomi ; Sasamoto, Hiromi ; Uchida, Takuyuki ; Nishida, Naoshi ; Tanaka, Noriaki ; Boland, Clement Richard ; Matsubara, Nagahide. / Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis. In: International Journal of Cancer. 2008 ; Vol. 122, No. 11. pp. 2429-2436.
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abstract = "O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair gene which is frequently methylated in colorectal cancer (CRC). However, it remains controversial whether methylation of specific CpG sequences within MGMT promoter leads to loss of its protein expression, and if MGMT methylation correlates with G to A transition mutations in KRAS. Two methylation sensitive regions (Mp and Eh region) of MGMT promoter were investigated in 593 specimens of colorectal tissue: 233 CRCs, 104 adenomatous polyps (AP), 220 normal colonic mucosa from CRC patients (N-C) and 36 normal colonic mucosa specimens obtained from subjects without colorectal neoplasia (N-N) by combined bisulfite restriction analysis (COBRA). The region-specific methylation data were compared to the MGMT protein expression, spectrum of KRAS mutations and other clinical features. Extensive (including both Mp and Eh) and partial (either Mp or Eh) MGMT methylation were found in 24.5{\%} and 11.6{\%} of CRCs, 3.8{\%} and 27.9{\%} of APs, 0.5{\%} and 7.7{\%} of C-Ns and 2.8{\%} and 2.8{\%} of N-Ns, respectively. Extensive methylation of MGMT promoter was primarily present in CRCs while partial methylation was common in APs. Extensive methylation of MGMT promoter was associated with loss/reduced protein expression (p <0.0001), as well as with G to A mutations in KRAS (p = 0.0017). We herein provide first evidence that extensive methylation of MGMT promoter region is essential for methylation-induced silencing of this gene. Our data suggest that MGMT methylation may evolve and spread throughout the promoter in a stepwise manner as the colonic epithelial cells progress through the classical-adenoma-cancer multistep cascade.",
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AU - Uchida, Takuyuki

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