High frequency of hypermethylation of p14, p15 and p16 in oral pre-cancerous lesions associated with betel-quid chewing in Sri Lanka
High frequency of hypermethylation of p14, p15 and p16 in oral pre-cancerous lesions associated with betel-quid chewing in Sri Lanka
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DOI：
10.1111/j.1600-0714.2008.00644.x
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发表时间：
2008-09-01
影响因子：
3.3
通讯作者：
Abiko, Yoshihiro
中科院分区：
文献类型：
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作者：
Takeshima, Maiko;Saitoh, Masato;Abiko, Yoshihiro
背景：口腔鳞状细胞癌和最常见的口腔癌前病变似乎与斯里兰卡人咀嚼槟榔的习惯有关。尽管口腔癌中肿瘤抑制基因的高甲基化已得到充分记录，但有关口腔癌前病变中高甲基化的信息却很少。在本研究中，我们研究了癌前病变（包括上皮发育不良和粘膜下纤维化）中p14、p15和p16的高甲基化。方法：所有样本均取自斯里兰卡有咀嚼槟榔习惯的患者。 64 名患者临床诊断为白斑，组织病理学诊断为轻度或重度不典型增生。 10 名患者被诊断为粘膜下纤维化，但无上皮发育不良。通过甲基化特异性 PCR 方法评估 CpG 岛高甲基化。使用抗p53抗体进行免疫组织化学染色。结果：在癌前病变中检测到高频率的p14、p15和p16高甲基化，而在正常上皮中未发现高甲基化。除轻度不典型增生中的 p16 外，高甲基化频率高于 p53 突变阳性染色频率。在任何病变中，p53 阳性反应与高甲基化之间均未观察到显着相关性。即使在 p53 阴性病变中，高甲基化也高度可检测到，这表明无论病变是否有 p53 突变，p14、p15 和 p16 都会发生高甲基化。 结论：本研究表明，高甲基化可能参与斯里兰卡与咀嚼槟榔相关的口腔癌前病变的发病机制。
BACKGROUND: Oral squamous cell carcinoma and the most common oral pre-malignancies appear to be related to the habit of betel-quid chewing in Sri Lanka. Although hypermethylation of the tumour suppressor genes in oral cancer have been well documented, little information has been available concerning hypermethylation in oral pre-cancerous lesions. In the present study, we investigated the hypermethylation of p14, p15 and p16 in pre-cancerous lesions including epithelial dysplasia and submucous fibrosis.METHODS: All samples were obtained from patients with a betel-quid chewing habit in Sri Lanka. Sixty-four patients were clinically diagnosed with leukoplakia, and histopathologically diagnosed with mild or severe dysplasia. Ten patients were diagnosed with submucous fibrosis without epithelial dysplasia. CpG island hypermethylation was assessed by a methylation-specific PCR method. Immunohistochemical staining was performed using anti-p53 antibodies.RESULTS: A high frequency of hypermethylation of p14, p15 and p16 was detected in the pre-cancerous lesions, although no hypermethylation was found in normal epithelium. The frequency of hypermethylation was higher than that of positive staining for p53 mutation except in the case of p16 in mild dysplasia. No significant correlation was observed between p53-positive reactions and hypermethylation in any lesions. The hypermethylation was highly detectable even in p53-negative lesions, suggesting that hypermethylation of p14, p15 and p16 occur regardless of whether the lesions have p53 mutations or not.CONCLUSIONS: The present study indicates that hypermethylation may be involved in the pathogenesis of oral pre-cancerous lesions associated with betel-quid chewing in Sri Lanka.