Hypermethylation of O6-Methylguanine-DNA Methyltransferase Promoter May Predict Nonrecurrence after Chemotherapy in Colorectal Cancer Cases

Takeshi Nagasaka, Gerald B. Sharp, Kenji Notohara, Takeshi Kambara, Hiromi Sasamoto, Hiroshi Isozaki, Donald G. MacPhee, Jeremy R. Jass, Noriaki Tanaka, Nagahide Matsubara

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Abstract

Purpose: Because O6-methylguanine-DNA methyltransferase (MGMT) plays an essential role in repairing DNA damage caused by environmental alkylating chemicals, we were interested in determining whether we could see any obvious changes in the properties of colorectal cancers (CRCs) in which the MGMT gene had been silenced by hypermethylation and hence in which very few MGMT protein molecules were being produced. Experimental Design: We used a methylation-specific PCR assay to determine the methylation status of the MGMT promoter in the DNA molecules extracted from CRC and nontumor tissue samples from 116 patients who had undergone CRC surgery and for whom clinical outcome information was available on file. Results: We found evidence of MGMT promoter hypermethylation in 26 of 90 CRC cases, and we noted that the later the stage at which a tumor was diagnosed, the less likely its MGMT promoter was to be methylated (P = 0.03, adjusting for chemotherapy), especially for stage D patients (P = 0.01). We also found that CRC patients with unmethylated MGMT promoters were much more likely to experience recurrence within 36 months than patients with hypermethylated MGMT promoters (crude odds ratio, 14.0; 95% confidence interval, 2.42-81.01). After adjustment for stage, CRC patients with unmethylated MGMT promoters who had been exposed to chemotherapy were found to have a 5.3-fold greater risk of recurrence than those who had no exposure to chemotherapy (95% confidence interval, 1.15-30.92). Conclusions: Hypermethylation of the MGMT promoter may be predictive of a low risk of recurrence in CRC patients receiving adjuvant chemotherapy.

Original languageEnglish
Pages (from-to)5306-5312
Number of pages7
JournalClinical Cancer Research
Volume9
Issue number14
Publication statusPublished - Nov 1 2003

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Methyltransferases
Colorectal Neoplasms
Drug Therapy
DNA
Recurrence
Methylation
O-(6)-methylguanine
Protein Methyltransferases
Confidence Intervals
Colorectal Surgery
Adjuvant Chemotherapy
DNA Damage
Research Design
Odds Ratio
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nagasaka, T., Sharp, G. B., Notohara, K., Kambara, T., Sasamoto, H., Isozaki, H., ... Matsubara, N. (2003). Hypermethylation of O6-Methylguanine-DNA Methyltransferase Promoter May Predict Nonrecurrence after Chemotherapy in Colorectal Cancer Cases. Clinical Cancer Research, 9(14), 5306-5312.

Hypermethylation of O6-Methylguanine-DNA Methyltransferase Promoter May Predict Nonrecurrence after Chemotherapy in Colorectal Cancer Cases. / Nagasaka, Takeshi; Sharp, Gerald B.; Notohara, Kenji; Kambara, Takeshi; Sasamoto, Hiromi; Isozaki, Hiroshi; MacPhee, Donald G.; Jass, Jeremy R.; Tanaka, Noriaki; Matsubara, Nagahide.

In: Clinical Cancer Research, Vol. 9, No. 14, 01.11.2003, p. 5306-5312.

Research output: Contribution to journalArticle

Nagasaka, T, Sharp, GB, Notohara, K, Kambara, T, Sasamoto, H, Isozaki, H, MacPhee, DG, Jass, JR, Tanaka, N & Matsubara, N 2003, 'Hypermethylation of O6-Methylguanine-DNA Methyltransferase Promoter May Predict Nonrecurrence after Chemotherapy in Colorectal Cancer Cases', Clinical Cancer Research, vol. 9, no. 14, pp. 5306-5312.
Nagasaka, Takeshi ; Sharp, Gerald B. ; Notohara, Kenji ; Kambara, Takeshi ; Sasamoto, Hiromi ; Isozaki, Hiroshi ; MacPhee, Donald G. ; Jass, Jeremy R. ; Tanaka, Noriaki ; Matsubara, Nagahide. / Hypermethylation of O6-Methylguanine-DNA Methyltransferase Promoter May Predict Nonrecurrence after Chemotherapy in Colorectal Cancer Cases. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 14. pp. 5306-5312.
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abstract = "Purpose: Because O6-methylguanine-DNA methyltransferase (MGMT) plays an essential role in repairing DNA damage caused by environmental alkylating chemicals, we were interested in determining whether we could see any obvious changes in the properties of colorectal cancers (CRCs) in which the MGMT gene had been silenced by hypermethylation and hence in which very few MGMT protein molecules were being produced. Experimental Design: We used a methylation-specific PCR assay to determine the methylation status of the MGMT promoter in the DNA molecules extracted from CRC and nontumor tissue samples from 116 patients who had undergone CRC surgery and for whom clinical outcome information was available on file. Results: We found evidence of MGMT promoter hypermethylation in 26 of 90 CRC cases, and we noted that the later the stage at which a tumor was diagnosed, the less likely its MGMT promoter was to be methylated (P = 0.03, adjusting for chemotherapy), especially for stage D patients (P = 0.01). We also found that CRC patients with unmethylated MGMT promoters were much more likely to experience recurrence within 36 months than patients with hypermethylated MGMT promoters (crude odds ratio, 14.0; 95{\%} confidence interval, 2.42-81.01). After adjustment for stage, CRC patients with unmethylated MGMT promoters who had been exposed to chemotherapy were found to have a 5.3-fold greater risk of recurrence than those who had no exposure to chemotherapy (95{\%} confidence interval, 1.15-30.92). Conclusions: Hypermethylation of the MGMT promoter may be predictive of a low risk of recurrence in CRC patients receiving adjuvant chemotherapy.",
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AU - Kambara, Takeshi

AU - Sasamoto, Hiromi

AU - Isozaki, Hiroshi

AU - MacPhee, Donald G.

AU - Jass, Jeremy R.

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N2 - Purpose: Because O6-methylguanine-DNA methyltransferase (MGMT) plays an essential role in repairing DNA damage caused by environmental alkylating chemicals, we were interested in determining whether we could see any obvious changes in the properties of colorectal cancers (CRCs) in which the MGMT gene had been silenced by hypermethylation and hence in which very few MGMT protein molecules were being produced. Experimental Design: We used a methylation-specific PCR assay to determine the methylation status of the MGMT promoter in the DNA molecules extracted from CRC and nontumor tissue samples from 116 patients who had undergone CRC surgery and for whom clinical outcome information was available on file. Results: We found evidence of MGMT promoter hypermethylation in 26 of 90 CRC cases, and we noted that the later the stage at which a tumor was diagnosed, the less likely its MGMT promoter was to be methylated (P = 0.03, adjusting for chemotherapy), especially for stage D patients (P = 0.01). We also found that CRC patients with unmethylated MGMT promoters were much more likely to experience recurrence within 36 months than patients with hypermethylated MGMT promoters (crude odds ratio, 14.0; 95% confidence interval, 2.42-81.01). After adjustment for stage, CRC patients with unmethylated MGMT promoters who had been exposed to chemotherapy were found to have a 5.3-fold greater risk of recurrence than those who had no exposure to chemotherapy (95% confidence interval, 1.15-30.92). Conclusions: Hypermethylation of the MGMT promoter may be predictive of a low risk of recurrence in CRC patients receiving adjuvant chemotherapy.

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