ASSOCIATION BETWEEN CIGARETTE-SMOKING AND MUTATION OF THE P53 GENE INSQUAMOUS-CELL CARCINOMA OF THE HEAD AND NECK

Background. Although epidemiologic studies have long associated tobacc o and alcohol use with the development of squamous-cell carcinoma of t he head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the p attern of mutations in the p53 gene in neoplasms from patients with sq uamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use. Methods. Sequence analysis of the conserved regions of t he p53 gene was performed in tumor samples from 129 patients with prim ary squamous-cell carcinoma of the head and neck. We then used statist ical analysis to identify any patient characteristics associated with mutation of the p53 gene. Results. We found p53 mutations in 42 percen t of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence i nterval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 t o 50 percent), and 17 percent of the patients who neither smoked nor d rank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent ) had p53 mutations (P = 0.001). (Two patients used alcohol but did no t smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentia lly representing endogenous mutations) within the p53 gene (5 of 5 mut ations; 95 percent confidence interval, 48 to 100 percent), whereas on ly 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001). Conclusions. In our study, a history of tobacco and alcoh ol use was associated with a high frequency of p53 mutations in patien ts with squamous-cell carcinoma of the head and neck. Preliminary evid ence linked cigarette smoking to p53 mutations at nonendogenous mutati on sites. Our findings suggest a role for tobacco in the molecular pro gression of squamous-cell carcinoma of the head and neck and support t he epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.