Aberrant p16INK4 expression related to clinical stage and prognosis in patients with pancreatic cancer.

Abstract

The p16 tumor suppressor gene is thought to play an important role in cell cycle regulation by encoding for protein products that can inhibit the progression from G1 to S phase in the cell cycle. Recently, the p16 gene has been found to be mutated or deleted in a variety of different types of primary human malignant tumors and human-derived malignant tumor cell lines. In this study, primary ductal pancreatic adenocarcinomas from 32 human patients were analyzed immunohistochemically for expression of p16 protein, with emphasis on the role of abberant p16 protein expression as a prognostic indicator. In addition, the same tumors were also assessed for p53 protein expression, AgNOR counts, and DNA ploidy. Nineteen out of the 32 cases (59%) showed positive immunoreactivity for p16 protein in their tumors and a significant association was found between lack of p16 protein expression, and both advancing clinical stage classification of disease, and poorer survival (p<0.05). The rate of positive immunoreactivity for p53 protein expression was 59%, however, no clear association was found between p53 protein expression, and either clinical stage of disease, or survival. These findings suggest that alteration of the p53 gene may be a relatively early event in pancreatic tumorigenesis, whereas alteration of the p16 gene is more likely to be correlated with tumor progression in pancreatic malignancies. Further survival analysis revealed that all five of the 32 cases that survived for three years or longer had positive immunostaining for p16 protein, and a relatively low level of AgNOR counts. In four out of five of these patients, the tumors also exhibited negative immunostaining for p53 protein and DNA diploidy. These findings suggest that molecular analysis of patient tumor sections may yield potentially useful prognostic indicators for patients undergoing surgical resection for pancreatic cancer.