Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma

Abstract

Purpose: KRAS mutations are found in f25% of lung adenocarcinomas inWestern countries and, as a group, have been 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. Experimental Design: 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. Results: KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 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. 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 smokingrelated (G!Tor G!C; P < 0.0001).Conclusions: Based on 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.Since the identification of somatic epidermal growth factor receptor (EGFR) mutations, there has been heightened interest in the molecular basis of lung cancer in patients who never smoked cigarettes (1 -3). Somatic mutations in EGFR have been identified in f15% of all patients with lung adenocarcinoma, with the proportion increasing to 50% in patients who never smoked cigarettes. There is an inverse relationship between cigarette smoking history and frequency of EGFR mutations, with the frequency of EGFR mutations decreasing significantly among patients who smoked more than 15 pack years (4). Such refined understanding of the relationship between smoking history and presence of EGFR mutations has allowed the design of clinical trials which use smoking history to enrich the number of patients with somatic EGFR mutations (5-7).In contrast to EGFR mutations, KRAS mutations were initially identified in patients with lung adenocarcinoma who had a history of heavy cigarette smoking and were thought to be uncommon in patients without a history of smoking cigarettes (8). These mutations are found in f25% of lung adenocarcinomas in western countries but are less common in Asian populations (9, 10). KRAS mutations have been associated with poor prognosis in resected non -small cell lung cancer (NSCLC; refs. 11-13), lack of survival benefit from adjuvant chemotherapy (14), and resistance to erlotinib or gefitinib (15). More than 95% of KRAS ...

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Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

“…While point mutations in codon 12 or 13 account for the majority of KRAS mutations (8), recent studies have reported that KRAS also undergoes copy number gain at chromosome 12p12 in 11% to 15% of lung tumors (9,10). RAS genes are members of the small GTPase super family (11) and function to propagate growth factor signaling through activation of c-RAF and phosphoinositide-3-kinase (PI3K) pathways.…”