The aberrant expression by the target genes of tumor supressor protein p53 in non- small cell lung cancer. A search for a new mechanism of carcinogenesis.

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While p53 overexpression is often associated with p53 mutaions, the abnormalities in downstream of p53 transactivation may also contribute to the overexpression and dysfunction of p53 protein. In this study, the expressions of p53, Mdm2, and p21WAF1/CIP1 were examined by immunohistochemistry, and the mutations of p21 and GADD45 were searched by PCR-SSCP in a cohort of 123 patients with NSCLC of all stages, incluging 71 primary lung tumors and 52 metastatic tumors. Sixty-three patients received potentially curative treatment (stages I,II and IIIA) and 60 patients palliative treatment (stages IIIB and IV). Of all tumors, 39% were positive for p53 (DO-7, Dako) and 18% were positive for Mdm2 (Ab-1, Oncogene Science). As for p21 (Ab-1, Oncogene Science), 75% of the tumors were negative while the rest of the tumors expressed variable amounts. While the expression of p53 and p21 was independent, Mdm2 appeared to be coexpressed with p53 (p2=0.013) and p21 (p2=0.001). In the patients treated with curarive intent, the probability of survival or development of metastases according to Kaplan-Meier method showed limited number of associations with p53 or Mdm2 expression. Cox proportional hazards model only associated the overexpression of p53 (p=0.0001) with shortened survival and the development of metastases in these patients. the results that no mutations were found in the coding region of p21 and GADD45, revealed the alterations of the p53 gene products are the main cause of the carcinogenesis. The heterogeneous expression of p53, Mdm2, and p21 in NSCLC suggested multiple mechanisms of transactivating or suppressing transactivation factors contributing to carcinogenesis.