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

Departments of Gastroenterological Surgery and Surgical Oncology [T. N., T. K., H. S., H. I., N. T., N. M.] and Pathology [K. N.], Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan [G. B. S., D. G. M.]; and Department of Pathology, McGill University, Montreal, Quebec, Canada [J. R. J.]

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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