TP53 mutations and survival in squamous-cell carcinoma of the head and neck

Abstract

Background: The abrogation of function of the tumor-suppressor protein p53 as a result of mutation of its gene, TP53, is one of the most common genetic alterations in cancer cells. We evaluated TP53 mutations and survival in patients with squamous-cell carcinoma of the head and neck.

Methods: A total of 560 patients with squamous-cell carcinoma of the head and neck who were treated surgically with curative intent were enrolled in our prospective multicenter, 7-year study. TP53 mutations were analyzed in DNA from the tumor specimens with the use of the Affymetrix p53 chip and the Surveyor DNA endonuclease and denaturing high-performance liquid chromatography. Mutations were classified into two groups, disruptive and nondisruptive, according to the degree of disturbance of protein structure predicted from the crystal structure of the p53-DNA complexes. TP53 mutational status was compared with clinical outcome.

Results: TP53 mutations were found in tumors from 224 of 420 patients (53.3%). As compared with wild-type TP53, the presence of any TP53 mutation was associated with decreased overall survival (hazard ratio for death, 1.4; 95% confidence interval [CI], 1.1 to 1.8; P=0.009), with an even stronger association with disruptive mutations (hazard ratio, 1.7; 95% CI, 1.3 to 2.4; P<0.001) and no significant association with nondisruptive mutations (hazard ratio, 1.2; 95% CI, 0.9 to 1.7; P=0.16). In multivariate analyses a disruptive TP53 alteration, as compared with the absence of a TP53 mutation, had an independent, significant association with decreased survival (hazard ratio, 1.7; 95% CI, 1.2 to 2.4; P=0.003).

Conclusions: Disruptive TP53 mutations in tumor DNA are associated with reduced survival after surgical treatment of squamous-cell carcinoma of the head and neck.

Figure 1. Overall Survival among Patients, According to Mutation Status and Mutation Category

Panel A shows Kaplan–Meier estimates of overall survival among the 196 patients with wild-type TP53 (of whom 99 died) and among the 224 patients with mutant TP53 (of whom 133 died). The median survival among patients with mutant TP53 was 3.2 years, as compared with 5.4 years among patients with wild-type TP53. Panel B shows the Kaplan–Meier estimates of overall survival among the 139 patients with nondisruptive TP53 mutations (of whom 76 died) and the 85 patients with disruptive TP53 mutations (of whom 57 died). The median survival among patients with disruptive mutations was 2.0 years, whereas that among patients with non-disruptive mutations was 3.9 years. Disruptive mutations were defined as nonconservative mutations located inside the key DNA-binding domain (the L2–L3 region) or stop codons in any region; nondisruptive mutations were defined as conservative or nonconservative mutations (excluding stop codons) outside the L2–L3 region.

Figure 2. Cumulative Incidence of Death among Patients with a Known Cause of Death According to Mutation Category

Of the patients who died from squamous-cell carcinoma of the head and neck, 44 had wild-type TP53, 39 had a nondisruptive TP53 mutation, and 38 had a disruptive TP53 mutation. Of the patients who died from other causes, 27 had wild-type TP53, 22 had a nondisruptive TP53 mutation, and 13 had a disruptive TP53 mutation. The mutation category was significantly associated with a cumulative risk of death from squamous-cell carcinoma of the head and neck (P = 0.002 with the use of the Gray test) but not with a cumulative risk of death from other causes (P = 0.87 with the use of the Gray test).