Chronic Obstructive Pulmonary Disease Is Not Associated with KRAS Mutations in Non-Small Cell Lung Cancer.

Ali Saber,Anke Van Den Berg,Arja Ter Elst,Maarten Van Den Berge,Anthonie J Van Der Wekken,Gerald S M A Kerner,T Jeroen N Hiltermann,Ed Schuuring,Harry J M Groen,Wim Timens,Melanie Königshoff

doi:10.1371/journal.pone.0152317

Abstract

Mutations in epithelial growth factor receptor (EGFR), as well as in the EGFR downstream target KRAS are frequently observed in non-small cell lung cancer (NSCLC). Chronic obstructive pulmonary disease (COPD), an independent risk factor for developing NSCLC, is associated with an increased activation of EGFR. In this study we determined presence of EGFR and KRAS hotspot mutations in 325 consecutive NSCLC patients subjected to EGFR and KRAS mutation analysis in the diagnostic setting and for whom the pulmonary function has been determined at time of NSCLC diagnosis. Information about age at diagnosis, sex, smoking status, forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) was collected. Chronic obstructive pulmonary disease(COPD) was defined according to 2013 GOLD criteria. Chi-Square, student t-test and multivariate logistic regression were used to analyze the data. A total of 325 NSCLC patients were included, 193 with COPD and 132 without COPD. COPD was not associated with presence of KRAS hotspot mutations, while EGFR mutations were significantly higher in non-COPD NSCLC patients. Both female gender (HR 2.61; 95% CI: 1.56–4.39; p<0.001) and smoking (HR 4.10; 95% CI: 1.14–14.79; p = 0.03) were associated with KRAS mutational status. In contrast, only smoking (HR 0.11; 95% CI: 0.04–0.32; p<0.001) was inversely associated with EGFR mutational status. Smoking related G>T and G>C transversions were significantly more frequent in females (86.2%) than in males (61.5%) (p = 0.008). The exon 19del mutation was more frequent in non-smokers (90%) compared to current or past smokers (36.8%). In conclusion, KRAS mutations are more common in females and smokers, but are not associated with COPD-status in NSCLC patients. EGFR mutations are more common in non-smoking NSCLC patients.

Highlights

Chronic obstructive pulmonary disease (COPD) is associated with lung cancer after accounting for other respiratory diseases and smoking [1,2]
For 1 out of 105 patients with a KRAS mutation, the type of mutation was inconclusive with a positive high resolution melting (HRM) PCR result, but with a wild type sequence based on the Sanger sequencing result
We found a significant relationship between smoking and COPD, 62.6% of current or past smokers had COPD, while only 18.2% of non-smokers had COPD (p

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is associated with lung cancer after accounting for other respiratory diseases and smoking [1,2]. The OR dropped to 6.8 after correction for smoking [5] This is consistent with the notion that COPD has been recognized as an independent risk factor for developing lung cancer [6]. KRAS mutations are observed more frequent in smoking patients with adenocarcinoma (5–40%) than in the other subtypes of lung cancer [7, 9]. Mutations in the kinase domain lead to activation of the EGFR pathway independent of binding to its ligand [16] These activating EGFR mutations are common in non-small cell lung cancer (NSCLC) with a frequency of about 10–15% in Caucasians [17,18].

Materials and Methods

Results

Discussion