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Prevalence and Spectrum of p53 Mutations Associated with Smoking in Breast Cancer¹

Department of Epidemiology, School of Public Health [K. C., C-K. T., R. M.], Lineberger Comprehensive Cancer Center [K. C., S. N. E., L. C., S. S. D., J. P., L. D., R. M.], and Department of Medicine, School of Medicine [L. D.], University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Comparative Molecular Pathology Unit, National Cancer Institute, Gaithersburg, Maryland 20877 [M. H.]; Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263 [J. G.]; Genome Institute of Singapore, National University of Singapore, Singapore 117640 [E. T. L.]; and School of Public Health, Queensland University of Technology, Brisbane 4059, Australia [B. N.]

To explore the role of smoking in breast cancer, we undertook a population-based study to evaluate the prevalence and spectrum of p53 mutations in the breast tumors of smokers and nonsmokers. We evaluated 456 archival invasive breast tumors for mutations in exons 4–8 of the p53 gene, using single-strand conformational polymorphism analysis and manual sequencing. Statistical analyses were performed to determine the association of p53 mutations with clinical and smoking characteristics. Of 108 mutations identified, 77 (71%) were point mutations and 31 (29%) were deletions or insertions. A higher prevalence of p53 mutations was found in the breast tumors of current smokers (36.5%; P = 0.02) compared with never smokers (23.6%), whereas fewer mutations were found in former smokers (16.2%; P = 0.09). After adjustment for age, race, menopausal status, clinical stage, tumor size, and family history of breast cancer, current smokers were significantly more likely to harbor any p53 mutation [odds ratio (OR), 2.11; 95% confidence interval (CI), 1.17–3.78], p53 transversions (OR, 3.37; 95% CI, 1.03–11.06), and G:CT:A transversions (OR, 10.53; 95% CI, 1.77–62.55) compared with never smokers. Stage at diagnosis did not account for the increase in p53 mutation-positive breast cancer among current smokers. Former smokers were also more likely than never smokers to harbor G:CT:A transversions (OR, 2.43; 95% CI, 0.37–15.73), although this association was not statistically significant. Among former smokers, the prevalence of p53 mutations varied with time since quitting: former smokers who quit smoking for longer than 1 year had a lower prevalence of p53 mutations (10.5% for 1–5 years and 12.9% for >5 years) than those who had stopped smoking within the year of their cancer diagnosis (26.3%). Our results indicate that cigarette smoking appears to modify the prevalence and spectrum of p53 mutations in breast tumors. Moreover, the difference in mutational spectra observed between smokers and nonsmokers is suggestive of the genotoxic effects of smoking in breast tissue.

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