TP53 and CDKN2a Mutations in Never-Smoker Oral Tongue Squamous Cell Carcinoma

Objectives/Hypothesis: To determine the incidence and clinical significance of TP53 and CDKN2a somatic mutations in never smokers with oral tongue squamous cell carcinoma (OTSCC). Study Design: Case series. Methods: Fifty-one paraffin-embedded tumors from never smokers with OTSCC were obtained. p53 and p16 expression was determined by immunohistochemical (IHC) staining. Tumor DNA was amplified by polymerase chain reaction, and direct sequencing and mutation analysis was performed. Statistical relationships among p53 and p16 IHC findings, TP53 and CDKN2a mutation status, and clinicopathologic characteristics were determined. Univariate and multivariate Cox models for survival were performed. Results: Sixteen tumors (31.4%) showed strong expression of p53 by IHC. There was no correlation between p53 status and clinicopathologic variables or survival outcomes. TP53 mutations were seen in 10 tumors (19.6%). Patients with TP53 mutations had higher tumor-node-metastasis (TNM) stage (P=0.049), worse tumor differentiation (P=0.025), earlier recurrence (P=0.024), and more often died from their disease (P=0.043) than those without mutations. Five tumors (9.8%) showed p16 positivity by IHC. There was no correlation between p16 status and clinicopathologic variables or survival. CDKN2a mutations were seen in four tumors (7.8%). Patients with CDKN2a mutations had earlier recurrence (P=0.019) and more often died from their disease (P=0.010) than those without mutations. Kaplan-Meier curves show worse disease-free survival (P=0.0162, P=0.0025) and overall survival (P=0.0095, P=0.0001) for TP53 and CDKN2a mutations, respectively. Multivariate analysis demonstrated that TP53 and CDKN2a mutations were independent predictors of disease-free survival (P=0.038 and P=0.039, respectively). Conclusions: TP53 and CDKN2a mutations in never-smoker OTSCC are associated with worse clinicopathologic characteristics and poorer survival outcomes.