p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma.
BACKGROUND
The p53 gene (also known as TP53) may be the most common genetic target involved in the malignant transformation of human cells. Direct sequence analysis has demonstrated that alteration of this gene occurs in approximately 45% of head and neck squamous cell carcinomas. The consequences of p53 mutations in these cancers with respect to tumor behavior and patient survival have not been rigorously determined.


OBJECTIVE
We evaluated the implications of p53 mutations in relation to the control of locoregional disease and overall survival following radiation therapy.


METHODS
Data from 110 consecutive patients with invasive disease who were treated with primary radiation therapy (given with curative intent) or with adjuvant radiation therapy (following complete surgical extirpation of gross disease) were included in the analysis. A 1.8-kilobase fragment of the p53 gene encompassing exons 5-9 was amplified from the DNA of stored (frozen) tumor specimens; the amplified DNA was cloned and sequenced by use of standard techniques. Overall survival and locoregional disease-free survival after the completion of radiation therapy were estimated by the Kaplan-Meier method; survival comparisons were made by use of the logrank test or proportional hazards regression models. Reported P values are two-sided.


RESULTS
Fortyeight (44%) of the 110 tumors had cells bearing p53 mutations. The risk of locoregional recurrence following either primary or adjuvant radiation therapy was significantly greater (i.e., the time to recurrence was shorter) for patients whose tumors contained mutant p53 genes (univariate model hazard ratio [HR] for p53 mutation versus wild-type = 2.2; 95% confidence interval [CI] = 1.2-4.1; P = .02). The presence of regional lymph node metastases (presence versus absence, HR = 2.0; 95% CI = 1.0-4.2; P = .05) and treatment type (primary radiation therapy versus surgery plus adjuvant radiation therapy, HR = 2.3; 95% CI = 1.2-4.3; P = .01) were also associated with greater risks of locoregional failure. The presence of p53 mutations and lymph node metastases and treatment with primary, as opposed to adjuvant, radiation therapy remained significant risk factors in multivariate regression analysis. No relationship was demonstrated between p53 status and overall survival (mutant versus wild-type, HR = 1.1; 95% CI = 0.6-2.1; P = .66); however, a relationship was shown for tumor stage and overall survival (stages III and IV [more advanced] versus stages I and II [less advanced], HR = 3.3; 95% CI = 1.0-10.8; P = .05). Mutation of the p53 gene was not associated with patient age, sex, tumor stage, primary tumor site, regional lymph node status, degree of tumor cell differentiation, or treatment method.


CONCLUSIONS
Mutation of the p53 gene is associated with an increased risk of locoregional failure in patients with invasive head and neck squamous cell carcinoma who are treated with radiation therapy.
Koch
W M
WM
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, MD 21205-2196, USA.
Brennan
J A
JA
Zahurak
M
M
Goodman
S N
SN
Westra
W H
WH
Schwab
D
D
Yoo
G H
GH
Lee
D J
DJ
Forastiere
A A
AA
Sidransky
D
D
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000628:therapy*; D004273:DNA, Neoplasm / Q000235:genetics; D018572:Disease-Free Survival; D016158:Genes, p53 / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D016019:Survival Analysis; D017211:Treatment Failure
D004273:DNA, Neoplasm