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O⁶-Methylguanine-DNA Methyltransferase Gene: Epigenetic Silencing and Prognostic Value in Head and Neck Squamous Cell Carcinoma

Departments of ¹ Pathology and ² Otolaryngology, University of Arkansas for Medical Sciences and John L. McClellan Memorial Veterans' Hospital, Little Rock, Arkansas; ³ College of Public Health, Sun-Yat Sen University, Guangzhou, People's Republic of China; and ⁴ Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee

Requests for reprints: Chun-Yang Fan, Department of Pathology, University of Arkansas for Medical Sciences and John L. McClellan Memorial Veterans' Hospital, 4300 West 7th Street (113/LR), Little Rock, AR 72205. Phone: (501) 257-6469; Fax: (501) 257-6430. E-mail: fanchunyang{at}uams.edu

Background: Alkylating N-nitroso compounds can interact directly with DNA, forming O⁶-alkylguanine, a DNA adduct proved to be mutagenic and carcinogenic if not sufficiently repaired. A specific DNA repair enzyme, O⁶-methylguanine-DNA methyltransferase (MGMT), can remove the alkyl group from the O⁶-position of the guanine, thereby preventing its mutagenic and carcinogenic effects. Inactivation of the MGMT gene in association with promoter hypermethylation results in persistence of O⁶-alkylguanine in DNA, leading to G:C to A:T transition mutation and these G:C to A:T transition mutations can inactivate p53 tumor suppressor gene or activate ras proto-oncogene. Methods: We analyzed MGMT promoter hypermethylation and protein expression patterns in 94 cases of primary head and neck squamous cell carcinoma (HNSCC) by methylation-specific PCR (MSP) and immunohistochemical staining. The results were then correlated with clinical follow-up data. Results: MGMT promoter hypermethylation was present in 17 of 94 patients (18.1%) and apparent loss of protein expression was seen in 19 of 93 HNSCC patients (20.4%). The presence of MGMT promoter hypermethylation was significantly correlated with loss of MGMT protein expression in HNSCC. Both MGMT promoter hypermethylation and loss of protein expression were significantly correlated to increased tumor recurrences and decreased patient survival, independent of other risk factors, such as tumor site, tumor size, nodal status, age, and chemoradiation therapy. Conclusions: MGMT promoter hypermethylation and apparent loss of protein expression are reliable and independent prognostic factors in HNSCC. The above study may also provide guideline or basis for applying alkylating antitumor agents to patients with HNSCC that display MGMT promoter hypermethylation and/or loss of MGMT protein expression.

Key Words: O⁶-methylguanine-DNA methyltransferase (MGMT) • head and neck squamous cell carcinoma (HNSCC) • promoter hypermethylation • epigenetic silencing • protein expression • patient survival

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