The p53 Codon 72 Polymorphism and Lung Cancer Risk

The p53 Codon 72 Polymorphism and Lung Cancer Risk1

Departments of Environmental Health (Occupational Health Program) [R. F., M-T. W., D. M., K. T. K., D. C. C.] and Cancer Cell Biology [K. T. K.], Harvard School of Public Health, Boston, Massachusetts 02115; Thoracic Surgery Unit, Department of Surgery [J. C. W.], and Pulmonary and Critical Care Unit, Department of Medicine [D. C. C.], Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114; University of California at San Francisco, Department of Epidemiology and Biostatistics, San Francisco, California 94143 [J. K. W.]

Abstract

The p53 tumor suppressor gene frequently is mutated in many forms of human carcinomas. A common polymorphism occurs at codon 72 of exon 4, with two alleles encoding either arginine (CGC) or proline (CCC). This p53 polymorphism reportedly is associated with lung cancer susceptibility. However, not all investigations have been consistent, and this hypothesized association remains controversial. We tested the hypothesis that the Pro/Pro genotype is associated with increased lung cancer risk in a large case-control study of lung cancer that included 482 cases and 510 controls from the Massachusetts General Hospital in Boston, Massachusetts. DNA from peripheral blood samples was examined by PCR-RFLP. Pro/Pro homozygotes were found more frequently in adenocarcinomas (cases, 16.4%; controls, 12.0%; P = 0.03). The prevalence of the Pro/Pro homozygous genotype increased in frequency with increasing pack-years of smoking. The combined susceptible genotype homozygous Pro/Pro and heterozygous Arg/Pro was associated with a 1.45-fold higher risk of adenocarcinoma compared with Arg/Arg genotype (95% confidence interval = 1.01–2.06; P = 0.04) after adjustment for relevant variables. Lung adenocarcinoma risk increased with the presence of one or both variant alleles across smoking strata. In addition, at each level of smoking (except nonsmoker and light smoker), the risk associated with smoking was higher for the population with the combined variant (Arg/Pro + Pro/Pro) genotype. The risk for the combined genotype was associated with tobacco exposure status. In conclusion, the codon 72 germ-line polymorphism (Arg/Pro) of the common tumor suppressor gene p53 contributes to heritable susceptibility for smoke-induced lung adenocarcinoma. The modifications by p53 polymorphism and pack-years resulted in an increased risk of the susceptible genotype to lung adenocarcinoma. The p53 gene may modulate the response to environment carcinogens and thereby affect the risk of developing lung adenocarcinoma.

Footnotes

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↵1 Supported by NIH Grants CA74386, ES/CA06409, ES8357, and ES00002.
↵2 To whom requests for reprints should be addressed, at Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. E-mail: dchris{at}hohp.harvard.edu
↵3 The abbreviations used are: OR, odds ratio; CI, confidence interval.
- Accepted August 7, 1900.
- Received January 11, 1900.
- Revision received June 14, 1900.