K-RAS Oncogene Mutation in Patients With Advanced Non-Small Cell Lung Cancer Associated With Exposure to Wood Smoke and Tobacco Smoking: Therapeutic Implications

Background:

Lung cancer is the leading cause of cancer-related death among men and women worldwide (1). In 2007, 213,380 new cases of lung cancer were registered; from these cases, 160,390 deaths were reported. This number represents 15% of the total cases and 29% of cancer-related deaths in the world. Only 13% of the patients with lung cancer survive for 5 years [surveillance epidemiology and end result (seer) statistics http://seer. cancer.gov/], therefore it still is a serious health problem (2). Clinically speaking, lung cancer is divided into two main categories that cover small cell lung cancer and non-small cell lung cancer (NSCLC). About 75% of all lung tumors are NSCLC, including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma (1). Despite the multimodal treatment using chemotherapy, radiotherapy and surgery there is a poor prognosis for locally advanced NSCLC. Survival rates for clinical stage IIIA is 64% at one year and between 23% and 30% after five years; for clinical stage IIIB 32% and 3% after one and five years, respectively (3). While advancements in the treatment of NSCLC have been made, few survival rate improvements have been achieved.

Tobacco smoking is considered the main cause of NSCLC, but there are other risk factors as well, such as the exposure to asbestos, radon, heavy metals, and wood smoke. The latter has been described as a human carcinogen and an important risk factor for the development of NSCLC. The frequency of exposure to wood smoke in patients with NSCLC is 28% (2). Current data indicates than lung cancer associated with tobacco smoking and the lung cancer associated with wood smoke exposure present different clinical characteristics, which suggests that they might also have different genetic alterations, which are a consequence of tumor etiology. Nevertheless, there are no significant molecular researches that make possible to determine the differences in the pattern of mutations in oncogenes involved in lung tumorigenesis, in relation to the risk factors accounted by the patient. Recent advances in the knowledge of cancer biology have led to the identification of various potential molecular targets that play a major role in the development and progression of the disease. One of the most extensively researched signaling pathways involved in the cell proliferation and survival is the one activated by the epidermal growth factor receptor (EGFR). When the epidermal growth factor (EGF) binds to the extracellular domain of EGFR the kinase property of the receptor is activated regulating the activation of different signaling pathways. One of these pathways leads to the activation of K-RAS, which at the same time activates the pathway of MAP kinase, involved in the proliferation, differentiation, migration, and survival of the cell (these are fundamental events in oncogenesis). Reports indicate that mutations in EGFR can be found in 51% of non-smoking patients (4) and in 10% of smoking patients, while mutations in K-RAS occur in 30% to 50% of the lung adenocarcinomas associated with tobacco.

Active mutations in K-RAS not only occur in NSCLC, but they also occur in >50% of the colorectal adenocarcinomas, 75% of pancreatic tumors, 48% of lung cancer, and 44% of adrenocortical tumors (5). These mutations seem to be an independent risk factor for the prognosis of malignant tumors, since more than 90% of them occur at the codon 12 of the K-RAS gene (6-8), and they are associated with lack of response to erlotinib (9), a tyrosine-kinase inhibitor. Our research team has recently reported that wood smoke is an independent factor for the survival and response to a treatment with erlotinib (10). This information strongly supports the hypothesis that lung cancer tumorigenesis results from different molecular mechanisms according to the smoker's stage (11) or other carcinogenic factors associated with the appearance of the malignant neoplasia, such as wood smoke exposure. Therefore, we believe that, compared to what has been reported in smoking patients, wood smoke could cause a different frequency and pattern of mutations in the K-RAS oncogene. It is of clinical relevance to determine whether the patients with NSCLC exposed to wood smoke present any differences in the frequency and the type of mutations in the K-RAS gene, with respect to both smoking and non-smoking patients.

Actually, a number of potential biological markers are being investigated with the aim of selecting patients who will receive more specific therapies and thus achieve better results regarding the response to treatment and overall survival. This is why the ability to detect K-RAS mutations associated with risk factors for NSCLC could represent a starting point for proposing different treatment approaches and benefiting the patients according to the specific characteristics of each tumor.