The Role Of ATM In The Carcinogenesis Of Oral Squamous Cell Carcinoma

Cancer threatens human health. According to the reports from the Ministry of Health P.R.China in 2002, cancer ranks the first of the main death reasons. The malignant tumor from oral maxillofacial region is one type of the common carcinoma, most of which is squamous cell carcinoma(SCC).Generally speaking, it is well accepted that cancer is a genetic disease of genome mutation. The accumulation of mutation is determined by at least 3 aspects: the exogenous or endogenous mutagens, DNA replication errors and the defects of DNA repair mechanism. With the increasing knowledge of DNA repair mechanism, the correlation of DNA repair and carcinogenesis has become one of the spotlights of tumor research.ATM (ataxia telangiectasis mutated, ATM) gene plays key roles in DNA double strand break repair. It is involved in the DNA damage recognition, damage signal transduction and producing biological effects which is important for the maintainance of genome integrity. Evidence indicated that ATM was mutated and inactive in various kinds of tumors. However, the correlateion between ATM and the carcinogensis of oral squamous cell carcinoma (OSCC) is still unclear. Therefore, the purpose of this study is to investigate the role of ATM gene in the carcinogenesis and progression of OSCC.In this research, a total of 57 formalin-fixed and paraffin-embeddedsamples were obtained from patients with hyperkeratosis(6), oral premalignant lesions(13), OSCC (32) and normal healthy controls(6). The expression of ATM protein in all of the samples was investigated by streptavidin-peroxidase (SP) immunohistochemistry (IHC) assay. Polymerase chain reaction was also performed to detect the loss of heterozygosity (LOH) in D11S2179 of ATM gene. In addition, the correlations between ATM and the clinical and histopathologyical characteristic were also investigated.The results showed that for immunohistochemistry assay, ATM-positive staining was much stronger in oral premalignant lesions with increased severity of epithetlial dysplasia than in normal controls and hyperkeratosis. 68.7% of OSCC showed normal or increased ATM expression, while 31.3% had decreased or absent ATM expression which was more likely in those with higher histopathological grade, clinical stage and lymph node metastasis. Significant differences were found between the group of decreased or absent ATM expression and that of normal or increased expression according to the histopathologyhical grade and lymph node metastasis state. PCR results displayed that none of the samples from oral premalignant lesions had abnormal changes in D11S2179, while 3 of the OSCC(14.3%) showed loss of heterozygosisty(LOH) and 2(6.25%) with microsatellite instability(MSI). Those 3 patients with LOH showed absent ATM expression.In all, these results suggest that the overexpression of ATM may contriute to prevent carcinogensis of OSCC. Moreover, ATM inactivation may be one of the genetic alterations of the molecular progression of OSCC.