MGMT promoter methylation and field defect in sporadic colorectal cancer

Lanlan Shen, Yutaka Kondo, Gary L. Rosner, Lianchun Xiao, Natalie Supunpong Hernandez, Jill Vilaythong, P. Scott Houlihan, Robert S Krouse, Anil P Rama Rao, Janine G Einspahr, Julie Buckmeier, David S Alberts, Stanley R. Hamilton, Jean Pierre J Issa

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Abstract

Background: Sporadic colorectal cancers often arise from a region of cells characterized by a "field defect" that has not been well defined molecularly. DNA methylation has been proposed as a candidate mediator of this field defect. The DNA repair gene O6 -methylguanine-DNA methyltransferase (MGMT) is frequently methylated in colorectal cancer. We hypothesized that MGMT methylation could be one of the mediators of field cancerization in the colon mucosa. Methods: We studied MGMT promoter methylation by three different bisulfite-based techniques in tumor, adjacent mucosa, and nonadjacent mucosa from 95 colorectal cancer patients and in colon mucosa from 33 subjects with no evidence of cancer. Statistical tests were two-sided. Results: MGMT promoter methylation was present in 46% of the tumors. Patients whose cancer had MGMT promoter methylation also had substantial MGMT promoter methylation in apparently normal adjacent mucosa. This methylation was seen with a quantitative assay in 50% (22/44; 95% confidence interval [CI] = 34% to 65%) of normal samples with MGMT promoter methylation in the adjacent tumors, 6% (3/51; 95% CI = 1% to 16%) of samples without MGMT methylation in adjacent tumors, and 12% (4/33; 95% CI = 3% to 28%) of control samples (P<.001 for comparison between each of the latter two groups and the first group). MGMT methylation was detected with a more sensitive assay in 94%, 34%, and 27% of these samples, respectively (P<.001). In grossly normal colonic mucosa of colon cancer patients, methylation was detected 10 cm away from the tumor in 10 of 13 cases. Tumors with MGMT promoter methylation had a higher rate of G-to-A mutation in the KRAS oncogene than tumors without MGMT promoter methylation (10/42 versus 3/46, P = .03). Using a sensitive mutant allele-specific amplification assay for KRAS mutations, we also found KRAS mutations in 12% (3/25; 95% CI = 2.5% to 31%) of colorectal mucosas with detectable MGMT methylation and 3% (2/64; 95% CI = 0.4% to 11%) of colorectal mucosas without MGMT methylation (P = .13). Conclusion: Some colorectal cancers arise from a field defect defined by epigenetic inactivation of MGMT. Detection of this abnormality may ultimately be useful in risk assessment for colorectal cancer.

Original languageEnglish (US)
Pages (from-to)1330-1338
Number of pages9
JournalJournal of the National Cancer Institute
Volume97
Issue number18
DOIs
StatePublished - Sep 2005

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Methyltransferases
Methylation
Colorectal Neoplasms
DNA
Mucous Membrane
DNA Methylation
Neoplasms
Confidence Intervals
Mutation
Colon
Oncogenes
Epigenomics
DNA Repair
Colonic Neoplasms
Alleles

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Shen, L., Kondo, Y., Rosner, G. L., Xiao, L., Hernandez, N. S., Vilaythong, J., ... Issa, J. P. J. (2005). MGMT promoter methylation and field defect in sporadic colorectal cancer. Journal of the National Cancer Institute, 97(18), 1330-1338. https://doi.org/10.1093/jnci/dji275

MGMT promoter methylation and field defect in sporadic colorectal cancer. / Shen, Lanlan; Kondo, Yutaka; Rosner, Gary L.; Xiao, Lianchun; Hernandez, Natalie Supunpong; Vilaythong, Jill; Houlihan, P. Scott; Krouse, Robert S; Rama Rao, Anil P; Einspahr, Janine G; Buckmeier, Julie; Alberts, David S; Hamilton, Stanley R.; Issa, Jean Pierre J.

In: Journal of the National Cancer Institute, Vol. 97, No. 18, 09.2005, p. 1330-1338.

Research output: Contribution to journalArticle

Shen, L, Kondo, Y, Rosner, GL, Xiao, L, Hernandez, NS, Vilaythong, J, Houlihan, PS, Krouse, RS, Rama Rao, AP, Einspahr, JG, Buckmeier, J, Alberts, DS, Hamilton, SR & Issa, JPJ 2005, 'MGMT promoter methylation and field defect in sporadic colorectal cancer', Journal of the National Cancer Institute, vol. 97, no. 18, pp. 1330-1338. https://doi.org/10.1093/jnci/dji275
Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. Journal of the National Cancer Institute. 2005 Sep;97(18):1330-1338. https://doi.org/10.1093/jnci/dji275
Shen, Lanlan ; Kondo, Yutaka ; Rosner, Gary L. ; Xiao, Lianchun ; Hernandez, Natalie Supunpong ; Vilaythong, Jill ; Houlihan, P. Scott ; Krouse, Robert S ; Rama Rao, Anil P ; Einspahr, Janine G ; Buckmeier, Julie ; Alberts, David S ; Hamilton, Stanley R. ; Issa, Jean Pierre J. / MGMT promoter methylation and field defect in sporadic colorectal cancer. In: Journal of the National Cancer Institute. 2005 ; Vol. 97, No. 18. pp. 1330-1338.
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abstract = "Background: Sporadic colorectal cancers often arise from a region of cells characterized by a {"}field defect{"} that has not been well defined molecularly. DNA methylation has been proposed as a candidate mediator of this field defect. The DNA repair gene O6 -methylguanine-DNA methyltransferase (MGMT) is frequently methylated in colorectal cancer. We hypothesized that MGMT methylation could be one of the mediators of field cancerization in the colon mucosa. Methods: We studied MGMT promoter methylation by three different bisulfite-based techniques in tumor, adjacent mucosa, and nonadjacent mucosa from 95 colorectal cancer patients and in colon mucosa from 33 subjects with no evidence of cancer. Statistical tests were two-sided. Results: MGMT promoter methylation was present in 46{\%} of the tumors. Patients whose cancer had MGMT promoter methylation also had substantial MGMT promoter methylation in apparently normal adjacent mucosa. This methylation was seen with a quantitative assay in 50{\%} (22/44; 95{\%} confidence interval [CI] = 34{\%} to 65{\%}) of normal samples with MGMT promoter methylation in the adjacent tumors, 6{\%} (3/51; 95{\%} CI = 1{\%} to 16{\%}) of samples without MGMT methylation in adjacent tumors, and 12{\%} (4/33; 95{\%} CI = 3{\%} to 28{\%}) of control samples (P<.001 for comparison between each of the latter two groups and the first group). MGMT methylation was detected with a more sensitive assay in 94{\%}, 34{\%}, and 27{\%} of these samples, respectively (P<.001). In grossly normal colonic mucosa of colon cancer patients, methylation was detected 10 cm away from the tumor in 10 of 13 cases. Tumors with MGMT promoter methylation had a higher rate of G-to-A mutation in the KRAS oncogene than tumors without MGMT promoter methylation (10/42 versus 3/46, P = .03). Using a sensitive mutant allele-specific amplification assay for KRAS mutations, we also found KRAS mutations in 12{\%} (3/25; 95{\%} CI = 2.5{\%} to 31{\%}) of colorectal mucosas with detectable MGMT methylation and 3{\%} (2/64; 95{\%} CI = 0.4{\%} to 11{\%}) of colorectal mucosas without MGMT methylation (P = .13). Conclusion: Some colorectal cancers arise from a field defect defined by epigenetic inactivation of MGMT. Detection of this abnormality may ultimately be useful in risk assessment for colorectal cancer.",
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T1 - MGMT promoter methylation and field defect in sporadic colorectal cancer

AU - Shen, Lanlan

AU - Kondo, Yutaka

AU - Rosner, Gary L.

AU - Xiao, Lianchun

AU - Hernandez, Natalie Supunpong

AU - Vilaythong, Jill

AU - Houlihan, P. Scott

AU - Krouse, Robert S

AU - Rama Rao, Anil P

AU - Einspahr, Janine G

AU - Buckmeier, Julie

AU - Alberts, David S

AU - Hamilton, Stanley R.

AU - Issa, Jean Pierre J

PY - 2005/9

Y1 - 2005/9

N2 - Background: Sporadic colorectal cancers often arise from a region of cells characterized by a "field defect" that has not been well defined molecularly. DNA methylation has been proposed as a candidate mediator of this field defect. The DNA repair gene O6 -methylguanine-DNA methyltransferase (MGMT) is frequently methylated in colorectal cancer. We hypothesized that MGMT methylation could be one of the mediators of field cancerization in the colon mucosa. Methods: We studied MGMT promoter methylation by three different bisulfite-based techniques in tumor, adjacent mucosa, and nonadjacent mucosa from 95 colorectal cancer patients and in colon mucosa from 33 subjects with no evidence of cancer. Statistical tests were two-sided. Results: MGMT promoter methylation was present in 46% of the tumors. Patients whose cancer had MGMT promoter methylation also had substantial MGMT promoter methylation in apparently normal adjacent mucosa. This methylation was seen with a quantitative assay in 50% (22/44; 95% confidence interval [CI] = 34% to 65%) of normal samples with MGMT promoter methylation in the adjacent tumors, 6% (3/51; 95% CI = 1% to 16%) of samples without MGMT methylation in adjacent tumors, and 12% (4/33; 95% CI = 3% to 28%) of control samples (P<.001 for comparison between each of the latter two groups and the first group). MGMT methylation was detected with a more sensitive assay in 94%, 34%, and 27% of these samples, respectively (P<.001). In grossly normal colonic mucosa of colon cancer patients, methylation was detected 10 cm away from the tumor in 10 of 13 cases. Tumors with MGMT promoter methylation had a higher rate of G-to-A mutation in the KRAS oncogene than tumors without MGMT promoter methylation (10/42 versus 3/46, P = .03). Using a sensitive mutant allele-specific amplification assay for KRAS mutations, we also found KRAS mutations in 12% (3/25; 95% CI = 2.5% to 31%) of colorectal mucosas with detectable MGMT methylation and 3% (2/64; 95% CI = 0.4% to 11%) of colorectal mucosas without MGMT methylation (P = .13). Conclusion: Some colorectal cancers arise from a field defect defined by epigenetic inactivation of MGMT. Detection of this abnormality may ultimately be useful in risk assessment for colorectal cancer.

AB - Background: Sporadic colorectal cancers often arise from a region of cells characterized by a "field defect" that has not been well defined molecularly. DNA methylation has been proposed as a candidate mediator of this field defect. The DNA repair gene O6 -methylguanine-DNA methyltransferase (MGMT) is frequently methylated in colorectal cancer. We hypothesized that MGMT methylation could be one of the mediators of field cancerization in the colon mucosa. Methods: We studied MGMT promoter methylation by three different bisulfite-based techniques in tumor, adjacent mucosa, and nonadjacent mucosa from 95 colorectal cancer patients and in colon mucosa from 33 subjects with no evidence of cancer. Statistical tests were two-sided. Results: MGMT promoter methylation was present in 46% of the tumors. Patients whose cancer had MGMT promoter methylation also had substantial MGMT promoter methylation in apparently normal adjacent mucosa. This methylation was seen with a quantitative assay in 50% (22/44; 95% confidence interval [CI] = 34% to 65%) of normal samples with MGMT promoter methylation in the adjacent tumors, 6% (3/51; 95% CI = 1% to 16%) of samples without MGMT methylation in adjacent tumors, and 12% (4/33; 95% CI = 3% to 28%) of control samples (P<.001 for comparison between each of the latter two groups and the first group). MGMT methylation was detected with a more sensitive assay in 94%, 34%, and 27% of these samples, respectively (P<.001). In grossly normal colonic mucosa of colon cancer patients, methylation was detected 10 cm away from the tumor in 10 of 13 cases. Tumors with MGMT promoter methylation had a higher rate of G-to-A mutation in the KRAS oncogene than tumors without MGMT promoter methylation (10/42 versus 3/46, P = .03). Using a sensitive mutant allele-specific amplification assay for KRAS mutations, we also found KRAS mutations in 12% (3/25; 95% CI = 2.5% to 31%) of colorectal mucosas with detectable MGMT methylation and 3% (2/64; 95% CI = 0.4% to 11%) of colorectal mucosas without MGMT methylation (P = .13). Conclusion: Some colorectal cancers arise from a field defect defined by epigenetic inactivation of MGMT. Detection of this abnormality may ultimately be useful in risk assessment for colorectal cancer.

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