Expression of Tumor Suppressor Gene p16INK4 Products in Primary Gastric Cancer

Publisher Website
Google Scholar
Abstract
Recent studies have shown that the cyclin-dependent kinase (CDK) inhibitor p27Kip1 represents an indicator for patients’ outcome in several human malignancies including gastric cancer. However, the clinicopathologic value of another class of CDK inhibitor, p16INK4, has not been determined. In a retrospective study, we examined the expression of p16INK4 by immunohistochemical assay of 80 samples of primary gastric cancers and their adjacent nonneoplastic mucosas. Less than 10% of non-tumor gastric mucosal cells were p16INK4 positive, whereas the expression of p16INK4 in gastric cancer cells varied widely from 0 to 100% (mean, 24.5%). The expression of p16INK4 was not seen in 11.3% (9/80) of the cancer cases, but in 65% (52/80) this protein was even overexpressed when compared with the nonneoplastic mucosa. A clinicopathologic survey indicated that a low or no expression of p16INK4 was associated with poorly differentiated carcinoma (p = 0.0133), but the level of expression did not correlate with other parameters including patients’ prognosis or with the expression of the pRb protein. In an effort to explore the underlying mechanism for the p16INK4-negative cases, a prospective study was also performed on 20 cases of gastric cancer to compare the level of the p16INK4 protein with the methylation status of the p16INK4 promoter. Gastric cancer tissues with methylation expressed significantly lower levels of the p16INK4 protein (p = 0.0013) and two of them lacked p16INK4 expression altogether, whereas all the cancer tissues without methylation expressed it. These findings suggest that the p16INK4 protein may be associated with differentiation of gastric cancer tissues and that methylation of the p16INK4 promoter may, in part, account for the loss of p16INK4 expression.