TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response

Abstract

Recent studies describing the mutational landscape of head and neck squamous cell carcinoma (HNSCC) on a genomic scale by our group and others, including The Cancer Genome Atlas, have provided unprecedented perspective for understanding the molecular pathogenesis of HNSCC progression and response to treatment. These studies confirmed that mutations of the TP53 tumor suppressor gene were the most frequent of all somatic genomic alterations in HNSCC, alluding to the importance of the TP53 gene in suppressing the development and progression of this disease. Clinically, TP53 mutations are significantly associated with short survival time and tumor resistance to radiotherapy and chemotherapy in HNSCC patients, which makes the TP53 mutation status a potentially useful molecular factor for risk stratification and predictor of clinical response in these patients. In addition to loss of wild-type p53 function and the dominant-negative effect on the remaining wild-type p53, some p53 mutants often gain oncogenic functions to promote tumorigenesis and progression. Different p53 mutants may possess different gain-of-function properties. Herein, we review the most up-to-date information about TP53 mutations available via The Cancer Genome Atlas-based analysis of HNSCC and discuss our current understanding of the potential tumor-suppressive role of p53, focusing on gain-of-function activities of p53 mutations. We also summarize our knowledge regarding the use of the TP53 mutation status as a potential evaluation or stratification biomarker for prognosis and a predictor of clinical response to radiotherapy and chemotherapy in HNSCC patients. Finally, we discuss possible strategies for targeting HNSCCs bearing TP53 mutations. J. Cell. Biochem. 117: 2682-2692, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: GAIN-OF-FUNCTION; HEAD AND NECK SQUAMOUS CELL CARCINOMAS; HNSCC; P53 MUTATION; p53.

Figure 1

The clinical, histological, and molecular pathogenesis of oral cancer. (A) Clinical features of the progression of oral cancer. (B) The histological progression from normal-appearing mucosa to invasive cancer. (C) The progression of oral cancer is concomitant with the genetic alterations of multiple tumor suppressor genes and oncogenes. LOH: loss of heterozygosity. (Courtesy of Jeoseh A. Califano, M.D.).

Figure 2

Histogram of number of cases with missense and nonsense TP53 mutations in HNSCC TCGA (n=510) by p53 codon position.

Figure 3

Overall survival probability for HNSCC patients in the TCGA data set (n=507) stratified by EAp53 scoring of missense TP53 mutations. High: high-risk missense mutation; Low: low-risk missense mutation; E: Event, which represents numbers of patients who passed away.

Figure 4

Overall survival probability for HNSCC patients in the TCGA data set (n=507) stratified by mutant and WT p53. E: Event, which represents numbers of patients who passed away.