TY - JOUR
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 - Prasad, Anil R.
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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U2 - 10.1093/jnci/dji275
DO - 10.1093/jnci/dji275
M3 - Article
C2 - 16174854
AN - SCOPUS:25144518262
SN - 0027-8874
VL - 97
SP - 1330
EP - 1338
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 18
ER -