Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use. Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene. We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not 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 (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 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). In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.
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