Frequency and distinctive spectrum of <i>KRAS</i> mutations in never smokers with lung adenocarcinoma

Abstract

8006 Background: KRAS mutations are found in ∼ 25% of lung adenocarcinomas in Western countries and, as a group, are strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib. In KRAS, transversions (substituting the purine G with a pyrimidine) are more common than transitions (substituting the purine G with A) and identify a molecular signature for the carcinogenic effects of cigarette smoke. Methods: We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas. Comparisons were made using Fisher’s exact test. Results: KRAS mutational analysis was performed on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12/81; 95% CI 8%-24%) of tumors from never smokers. Twenty-two% (69/316; 95% CI 17%-27%) of tumors from former smokers, and 25% (21/85; 95% CI 16%-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. When the type of KRAS mutation was examined, never smokers were significantly more likely than former or current smokers to have a transition mutation (G–>A) rather than the transversion mutations known to be smoking related (G–>T or G–>C; p<0.0001). Conclusions: Based upon our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study. Mutation Nucleotide Former/current Never Total G12A GGT–>GCT 13 0 13 G12C GGT–>TGT 38 0 38 G12V GGT–>GTT 20 1 21 G13C GGC–>TGC 2 0 2 G13D GGC–>GAC 1 0 1 G12D GGT–>GAT 15 10 25 G12S GGT–>AGT 1 1 2 Total 90 12 No significant financial relationships to disclose.