The p16 (CDKN2a/INK4a) Tumor-Suppressor Gene in Head and Neck Squamous Cell Carcinoma: A Promoter Methylation and Protein Expression Study in 100 Cases

Abstract

The p16 (CDKN2a/INK4a) gene is an important tumor-suppressor gene, involved in the p16/cyclin-dependent kinase/retinoblastoma gene pathway of cell cycle control. The p16 protein is considered to be a negative regulator of the pathway. The gene encodes an inhibitor of cyclin-dependent kinases 4 and 6, which regulate the phosphorylation of retinoblastoma gene and the G1 to S phase transition of the cell cycle. In the present study, p16 gene promoter hypermethylation patterns and p16 protein expression were analyzed in 100 consecutive untreated cases of primary head and neck squamous cell carcinoma by methylation-specific PCR and immunohistochemical staining. The p16 promoter hypermethylation and apparent loss of p16 protein expression were detected in 27% and 74% of head and neck squamous cell carcinoma, respectively. By χ2 test, history of alcohol or tobacco use was significantly correlated with the loss of p16 protein expression (P = .005 and.05, respectively). When patient follow-up data were correlated with various clinical and molecular parameters, tumor size and nodal and clinical stage were the strongest prognostic predictors for disease-free survival (tumor recurrence) and for cause-specific and overall survival in patients with head and neck squamous cell carcinoma. Neither p16 promoter hypermethylation nor apparent loss of p16 protein expression appears to be an independent prognostic factor, although loss of p16 protein may be used to predict overall patient survival in early-stage head and neck squamous cell carcinoma.