共济失调毛细血管扩张综合征突变基因与口腔黏膜癌变的相关研究

Role of ataxia telangiectasis mutated in the oncogenesis of oral squamous cell carcinoma

目的研究共济失调毛细血管扩张综合征突变基因(ATM)在口腔黏膜癌变过程中的作用。方法选取上皮单纯增生,轻、中、重度上皮异常增生,口腔黏膜鳞状细胞癌及正常口腔黏膜标本共61例,采用免疫组织化学SP法和聚合酶链反应方法,观察口腔黏膜癌变过程中ATM蛋白表达与基因杂合性缺失情况以及其与临床病理特征的关系。结果上皮异常增生组平均染色强度高于正常对照组,差别有统计学意义(P<0.05)。在口腔鳞癌中,22例(68.8%)ATM蛋白表达正常或升高,10例(31.3%)ATM蛋白表达降低或缺失;经统计学分析,ATM蛋白表达正常或升高组与ATM蛋白表达降低或缺失组两组分别在病理分级与淋巴结转移两方面的差异有统计学意义(P<0.05);PCR结果表明,上皮异常增生中未发现异常改变,而口腔鳞状细胞癌中,3例(9.38%)发生杂合性缺失,2例(6.25%)发生微卫星不稳定,发生杂合性缺失的3例病例ATM蛋白表达均缺失。结论ATM在上皮异常增生中表达升高可能有利于消除基因组不稳定,阻止癌变发生;而ATM基因失活可能是促使口腔鳞癌恶性演进的基因改变之一。

Objective To investigate the role of ataxia telangiectasis mutated （ATM） gene in the oncogenesis and progression of oral squamous cell carcinoma （OSCC）. Methods A total of 61 formalin-fixed and paraffin-embedded samples were obtained from patients with hyperkeratosis, oral leukoplakia, OSCC and normal healthy controls. The expression of ATM protein in all of the samples was investigated by streptavidin-peroxidase immunohistochemistry assay. PCR was also performed to detect the loss of heterozygosity（LOH） in Dlls2179 of ATM gene. The correlations between ATM and the clinical and histopathological characteristics were also investigated. Results The results indicated that the ATM expression was increased in oral premalignant lesions （P〈0.05）. For OSCC, 68.8% samples showed normal or increased ATM expression, while 31.3% had decreased or absent ATM expression. Significant differences were found between the group of decreased or absent ATM expression and that of normal or increased expression over the histopathological grade and lymph node metastasis state. PCR results displayed that none of the samples from oral premalignant lesions showed abnormal changes, while 3 of the OSCC （9.38%） showed loss of heterozygosity （LOH） and 2 （6.25%） with microsatellite instability （MSI）. Those 3 samples of LOH showed absent ATM expression. Conclusion These findings indicated that the over expression of ATM may contribute to prevent carcinogenesis of OSCC. ATM inactivation may be one of the genetic alterations of the molecular progression of OSCC.