© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 23, 2032-2038,
December 1, 1999
© 1999 Oxford University Press
REPORTS |
Implications and Prognostic Value of K-ras Mutation for Early-Stage Lung Cancer in Women
Affiliations of authors: H. H. Nelson, K. T. Kelsey, Department of Cancer Cell Biology, Harvard School of Public Health, Boston, MA; D. C. Christiani, Occupational Health Program, Harvard School of Public Health, and Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston; E. J. Mark (Department of Pathology), J. C. Wain (Thoracic Surgery Unit, Department of Surgery), Massachusetts General Hospital, Harvard Medical School; J. K. Wiencke, Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics, University of California at San Francisco.
Correspondence to: Karl T. Kelsey, M.D., M.O.H., Department of Cancer Cell Biology, Harvard School of Public Health, 665 Huntington Ave., Bldg. 1, Rm. 207, Boston, MA 02115-6021.
BACKGROUND: Because there is no clear consensus as to the predictive value of K-ras gene mutation for survival in patients with lung cancer, we examined the occurrence of K-ras mutations in a large, prospective case series of non-small-cell lung cancer (NSCLC). Our goals were to define the patient characteristics associated with K-ras mutation and to determine whether mutation of this gene might be a biomarker of patient prognosis. METHODS: Consecutive, newly diagnosed patients with lung cancer treated with potentially curative resection over a 4-year period were recruited for study. The mutation status of K-ras codon 12 in each patient's tumor DNA was determined by means of polymerase chain reaction-restriction fragment length polymorphism analysis of archived pathology specimens. Analyses were restricted to adenocarcinoma. RESULTS: There was a statistically significant association between female sex and K-ras mutation after adjustment for carcinogen exposures (odds ratio = 3.3; 95% confidence interval [CI] = 1.3-7.9); mutations were found only in smokers. Comparison of Kaplan-Meier curves indicated a strong association between K-ras mutation and decreased patient survival (two-sided P = .009); analysis stratified by pathologic staging groups revealed that this association was statistically significant only for stage I tumors (two-sided P = .002). Cox proportional hazards modeling indicated that K-ras codon 12 mutation was a statistically significant predictor of patient survival, after adjustment for the effects of age, sex, and stage (risk ratio = 1.8; 95% CI = 1.1-3.1). CONCLUSIONS: After adjustment for environmental exposures, non-small-cell lung tumors in women appear to be more likely than those in men to harbor K-ras mutations, suggesting a possible role of estrogen exposure in either the initiation or the selection of K-ras mutant clones in adenocarcinoma. In addition, our data suggest that K-ras codon 12 mutation is a marker of aggressive NSCLC, as evidenced by its association with decreased patient survival, particularly for early-stage disease.
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