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© 2005 Oxford University Press
ARTICLE |
MGMT Promoter Methylation and Field Defect in Sporadic Colorectal Cancer
Affiliations of authors: Departments of Leukemia (LS, YK, NSH, JV, J-PJI), Biostatistics and Applied Biomathematics (GLR, LX), and Pathology (PSH, SRH), The University of Texas at M. D. Anderson Cancer Center, Houston, TX; Departments of Surgery (RSK) and Pathology (ARP), University of Arizona, Tucson, AZ, and Southern Arizona Veterans Affairs Health Care System, Tucson, AZ; Arizona Cancer Center (JGE, JB, DSA), University of Arizona, Tucson, AZ
Correspondence to: Jean-Pierre Issa, MD, Department of Leukemia, M. D. Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: jpissa{at}mdanderson.org).
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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- DNA Methylation, Field Effects, and Colorectal Cancer
- Edward Giovannucci and Shuji Ogino
J Natl Cancer Inst 2005 97: 1317-1319.[Extract] [Full Text] [PDF]
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