Smoking history and lung carcinoma: KRAS mutation is an early hit in lung adenocarcinoma development
Introduction
Smoking is the major etiologic factor in lung cancer and associated with the following major histological subtypes: small cell carcinoma, non small cell lung cancer, squamous cell carcinoma and adenocarcinoma.
In smokers with an adenocarcinoma of the lung KRAS mutations occur more frequently than in tumours from non-smokers [1], [2], [3], [4], [5]. It has been demonstrated in a number of studies that KRAS mutations occur early in the development of pulmonary adenocarcinomas [6] and are detectable in precursor lesions of atypical adenomatous hyperplasia [7].
Smoking is considered to be the dominant carcinogenesis initiating agent in the development of lung cancer, and KRAS mutations are most likely one of the first molecular events and have been demonstrated after more than 15 years of quitting smoking [8]. However, the unanswered question is whether the quitting smoking time (QST) in ex-smokers with pulmonary adenocarcinoma, is longer for those with KRAS mutation than those without this mutation. In a small study by Westra et al. the presence of KRAS mutations appeared to be independent of duration of abstinence from smoking [8]. The aim of this study was to compare KRAS mutation analysis with smoking status within a subset of the EUELC recruited population. In the EUELC multicenter study, patients with lung cancer were interviewed for a wide range of epidemiological and clinical parameters, including smoking history. In addition, biological samples were collected in a central EU Biobank based in Liverpool, UK [9]. From this population a cohort of patients with progressive disease and disease free post surgery was selected. The time since quitting smoking was longer for patients with KRAS mutation than for those without KRAS mutation, suggesting that KRAS mutation is an early event in lung carcinogenesis.
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Materials and methods
Lung cancer cases were collected by 10 different centres in a EU framework 5 funded prospective study [9]. All patients were interviewed around the time of lung cancer diagnosis and asked to complete a detailed epidemiological/clinical questionnaire which also included smoking status. 913 patients were recruited into the EUELC and a nested case study was set up for patients with progressive disease (PD) and disease free (DF) status.
Progressive disease (PD) are patients with a history of a
Results
The clinical data are shown in Table 1. KRAS analyses showed mutations in 40 (17%) of the 233 cases. 39 of the 40 (97.5%) mutated cases were adenocarcinomas.
The type of mutations were TGT n = 26, GTT n = 9, AGT n = 1 and GAT n = 4, respectively. One of the patients had a double mutation GTT plus GCT. Note that most mutations were transversion mutations (88%). KRAS mutations were not associated with disease progression (p = 0.36).
The clinical variables related to the KRAS status are shown in Table 2. No
Discussion
This study demonstrates that the quitting smoking time (QST) in patients with lung cancer was longer for those with KRAS mutations than without KRAS mutations. From these results it may be argued that KRAS mutations are a very early event in carcinogenesis of pulmonary adenocarcinomas and this is in agreement with animal model studies suggesting that KRAS mutations occur early in lung tumour [16], [17], [18], [19], [20], [21].
The QST was not found to be normally distributed as may be seen from
Summary
Time to quit smoking before the development of lung cancer was longer for patients with KRAS mutations than those without, supporting the notion that the presence of a KRAS mutation is a early and dominant effect.
Conflict of interest
The authors have no financial disclosures on this subject.
The Research Project was supported by an EU Framework 5 grant (QLG1-CT-2002-01735).
The sponsor had no involvement in the study design, collection, analysis or interpretation of data; writing of the manuscript; or decision to submit the manuscript for publication.
Acknowledgements
The authors wish to thank all of the patients who agreed to participate in this European lung cancer research project.
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Former address: Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
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see Appendix table.