Prognostic Significance of Truncating TP53 Mutations in Head and Neck Squamous Cell Carcinoma

Purpose: TP53 is a key gene in cellular homeostasis and is frequently mutated in head and neck squamous cell carcinoma (HNSCC). There is a variety of TP53 mutations, each with its own biological and clinical implication. Aim of the study was to assess the prognostic significance of TP53 mutations in HNSCCs and to identify the most relevant mutation. Experimental Design: TP53 mutation status was investigated in 141 consecutive HNSCCs treated by surgery with radiotherapy when indicated and with a known human papilloma virus status. The type of mutation was correlated with overall and progression-free survival in a multivariate two-sided Cox regression analysis with wild type as reference. Results: A TP53 mutation was found in 88 (62.4%) of the carcinomas and was not significantly associated with overall survival (HR = 1.65, P = 0.11). Patients with a mutation resulting in a truncated protein (n = 36, 25.5%) had a significantly worse overall survival (HR = 2.54, P = 0.008) and progression-free survival (HR = 2.65, P = 0.002). Four of these mutations were at a splice site, 13 were nonsense mutations (produces stop codon), and 19 were insertions or deletions resulting in a frameshift. After multivariate analysis, a truncating mutation remained a significant prognosticator. A missense (i.e., nontruncating) mutation did not influence prognosis. Other ways of classification (disruptive vs. nondisruptive, hotspot vs. nonhotspot, and DNA binding vs. non-DNA binding) were less discriminative. Conclusion: In HNSCCs, a truncating TP53 mutation is associated with a poor prognosis. This patient group seems as a target population for adjuvant therapy with chemoradiation or viral vector-mediated TP53 gene transfer. Clin Cancer Res; 17(11); 3733-41. (C)2011 AACR.