Association between Cigarette Smoking and Mutation of the p53 Gene in Squamous-Cell Carcinoma of the Head and Neck
Joseph A. Brennan, M.D., Jay O. Boyle, M.D., Wayne M. Koch, M.D., Steven N. Goodman, M.D., Ph.D., Ralph H. Hruban, M.D., Yolanda J. Eby, M.S., Marion J. Couch, M.D., Ph.D., Arlene A. Forastiere, M.D., and David Sidransky, M.D.
Background Although epidemiologic studies have long associatedtobacco and alcohol use with the development of squamous-cellcarcinoma of the head and neck, the molecular targets of thesecarcinogens have yet to be identified. We performed a molecularanalysis to determine the pattern of mutations in the p53 genein neoplasms from patients with squamous-cell carcinoma of thehead and neck and a history of tobacco or alcohol use.
Methods Sequence analysis of the conserved regions of the p53gene was performed in tumor samples from 129 patients with primarysquamous-cell carcinoma of the head and neck. We then used statisticalanalysis to identify any patient characteristics associatedwith mutation of the p53 gene.
Results We found p53 mutations in 42 percent of the patients(54 of 129). Fifty-eight percent of the patients who smokedcigarettes and used alcohol (37 of 64; 95 percent confidenceinterval, 45 to 70 percent), 33 percent of the patients whosmoked but abstained from alcohol (13 of 39; 95 percent confidenceinterval, 19 to 50 percent), and 17 percent of the patientswho neither smoked nor drank alcohol (4 of 24, 95 percent confidenceinterval, 5 to 37 percent) had p53 mutations (P = 0.001). (Twopatients used alcohol but did not smoke, and neither had a p53mutation.) Furthermore, 100 percent of the mutations in thepatients who neither drank nor smoked occurred at sites containingcytidine phosphate guanosine dinucleotides (potentially representingendogenous mutations) within the p53 gene (5 of 5 mutations;95 percent confidence interval, 48 to 100 percent), whereasonly 23 percent of those in cigarette smokers consisted of suchchanges (12 of 53 mutations; 95 percent confidence interval,12 to 36 percent; P = 0.001).
Conclusions In our study, a history of tobacco and alcohol usewas associated with a high frequency of p53 mutations in patientswith squamous-cell carcinoma of the head and neck. Preliminaryevidence linked cigarette smoking to p53 mutations at nonendogenousmutation sites. Our findings suggest a role for tobacco in themolecular progression of squamous-cell carcinoma of the headand neck and support the epidemiologic evidence that abstinencefrom smoking is important to prevent head and neck cancer.
Source Information
From the Department of Otolaryngology–Head and Neck Surgery, Division of Head and Neck Cancer Research (J.A.B., J.O.B., W.M.K., Y.J.E., M.J.C., D.S.), the Oncology Center (S.N.G., A.A.F., D.S.), and the Division of Biostatistics (S.N.G.), Johns Hopkins University School of Medicine; and the Department of pathology, Johns Hopkins Hospital (R.H.H.) — both in Baltimore.
Address reprint requests to Dr. Sidransky at the Department of Otolaryngology–Head and Neck Surgery, 818 Ross Research Bldg., 720 Rutland Ave., Baltimore, MD 21205-2196.
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