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  • p is a tumor suppressor gene that inhibits cyclin


    p16 is a tumor-suppressor gene that inhibits cyclin-dependent kinase 4 and 6 activities and arrests the dmag in the G1 phase. Aberrant methylation and mutation of p16/MTS1 in OSCC of patients was found in our previous study. Moreover, the frequency of hypermethylation of p16 from the present study was 67.2%. This frequency is much higher than that in other countries such as the US and Japan, the frequencies of which are in the range of 21–47%.26, 27, 28 However, the hypermethylation frequency we found is strikingly similar to the p16 frequency of methylation of 66.7% among Indian subjects. These may be caused by ethnic and gender differences. The loss of p16 through p16 promoter methylation in our patients may have caused loss of function during tumor development. The hypermethylation of p16 of the primary tumor was also found to have slightly increased the metastasis rate in our cancer patients, but we could not establish statistical significance. This finding concurs with that of Maruya, who reported that p16 is less likely to be related to lymph node metastasis. Promoter hypermethylation of DAPK was also found in 45.3% of primary OSCC tissues in our study. This protein is a mediator of apoptosis induced by interferon-γ. Our finding is similar to that of Sanchez-Cespedes et al., who observed a positive correlation between the methylation of DAPK and the presence of lymph node metastases in patients with head and neck cancer. We believe that promoter hypermethylation of the DAPK gene can cause potential metastasis in OSCC primary tumors. Hypermethylation of MGMT in tumors with metastasis was observed in our study. MGMT is a DNA repair protein that removes adducts from O(6)alkyl G in DNA. If not removed, adducts are mispaired with T[spell out?] during DNA replication, resulting in G-to-A mutations. Thus, loss of MGMT will cause increased mutation rates. Hypermethylation of MGMT is closely associated with point mutations of K-ras at codons 12 and 13, lymph node invasion, tumor stage, and disease-free survival. We found a significant correlation between the methylation of MGMT and the development of metastases. The promoter region of the detoxifying gene, GSTP1, is commonly hypermethylated in the promoter region in prostate adenocarcinoma and hepatocellular carcinoma,38, 39 but it was not hypermethylated in either oral cancer tissue, adjacent mucosa, or normal oral mucosa, as previously reported. The regulation of GSTP1 expression in OSCC might not occur through promoter methylation.
    Acknowledgments This study was supported by grants from Taichung Veterans General Hospital (TCVGHC9301) and the National Science Council (NSC93-2314-B-075A-016).
    Introduction Buccal cancer rapidly increases its incidence in Taiwan. Clinically, buccal cancer characterizes a low neck nodal involvement but high primary tumor aggressiveness, representing a unique disease entity.[2], [3], [4] Radical surgery is the initial treatment of choice in patients with resectable disease; however, cancer recurrence is not uncommon after radical surgery alone.[2], [5] Thus, post-operative radiotherapy (RT) with or without chemotherapy is recommended for patients with adverse features, such as pT3-4, pN1-3, and positive but not close surgical margin. The role of unexpected close pathological margin after radical surgery may be underestimated. First, unexpected close surgical margin has been proposed to represent, at least partly, the intrinsic bio-aggressiveness of cancer cells. Second, patients with close margin are at a higher risk for cancer recurrence than patients with wide margin.[8], [9], [10], [11] However, close margin alone does not independently guide post-operative therapies.[5], [6], [12], [13] This discrepancy reveals a clinical debate. Further stratification in this subgroup of patients is essential. In this regard, we previously investigated resected buccal cancer patients who had a close surgical margin of⩽3 mm. We observed that very close surgical margin of⩽1 mm may be a good stratifying factor, but this pathological factor alone fails to predict overall survival. Thus, exploring a bio-predictor to complement the pathological factor is reasonable for further stratifying this group of patients.[7], [14], [15]