Implications and prognostic value of K-ras mutation for early-stage lung cancer in women

• Published in: JNCI : Journal of the National Cancer Institute 1999-12, Vol.91 (23), p.2032-2038
• Main Authors: NELSON, H. H, CHRISTIANI, D. C, MARK, E. J, WIENCKE, J. K, WAIN, J. C, KELSEY, K. T
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Aged; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Female; Genes, ras; Humans; K-ras gene; Lung cancer; lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Medical research; Medical sciences; Middle Aged; Mutation; Neoplasm Staging; Pneumology; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Prognosis; Prospective Studies; Regression Analysis; Sex Factors; Statistics, Nonparametric; Survival Analysis; Tumors of the respiratory system and mediastinum; Women
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/91.23.2032

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. 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. 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). 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.