Lung cancer is a significant worldwide health problem, accounting for more than 1.8 million new cases estimated in 2012 and 1.6 million cancer-related deaths annually[1]. The two main types are: small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). NSCLC comprises about 85% of all lung cancer cases, which have totally different etiology and treatment options[2]. NSCLC mainly includes squamous cell carcinoma, adenocarcinoma and large cell carcinoma. When patients are diagnosed in the early stages of NSCLC, the survival rates are relatively higher after a surgical resection. In patients with an untreated metastatic NSCLC present an overall survival (OS) rate in one year of only 10%, with a median survival of around 4 to 5 months[1].
Over the years, many genes/proteins have been discovered to play a key role in carcinogenesis[3]. RAS proteins are among the most commonly mutated cancer causing agents in humans and remain a difficult pharmaceutical target[4]. Members of the RAS family are low molecular weight monomeric, GTP-binding proteins that play a crucial role as a major component of cellular networks controlling various signaling pathways: growth regulation, proliferation, survival, differentiation, adhesion, cytoskeletal rearrangements, motility and cell survival[5, 6]. Previous research have improved the understanding of the structure, processing and signaling pathways of RAS in cancer cells and opened up new avenues for inhibiting RAS function[4, 5]. Abnormally activated RAS proteins regulate the function of major signaling pathways involved in the initiation and development in one-third of human cancers [3, 7, 8]. RAS proteins act as a cellular switch that is turned on by extracellular stimuli, resulting in the transient formation of an active, GTP-bound form of RAS that activates various signaling pathways which regulate basic cellular processes.
RAS genes family comprise of three RAS protooncogenes such as HRAS, KRAS and NRAS encoded four isoforms: NRAS, HRAS, KRAS4A and KRAS4B, the last two arising from alternative splicing variants of the KRAS gene[4]. The irreversible changes in the genetic content of a cell are a major cause of carcinogenesis as it can modulate both gene expression and the function of proteins involved in the regulation of cell growth and differentiation[3, 5]. RAS mutations have quite different patterns and vary with cancer. An oncogenic alteration in KRAS gene is the most frequent in pancreatic cancer, colorectal cancer and lung cancer, while mutated HRAS is the most common in dermatological, head and neck cancers. The NRAS mutations are often detected in hematological malignancies [3]. Since RAS genes are among the earliest mutated genes in various cancers, understanding how these mutation patterns arise can help not only understand how the cancer begins, but also the factors influencing the event that impact prevention and cancer treatment[7]. Till now, two general approaches have been explored for inhibiting RAS activity with small molecules: compounds that bind directly to RAS protein and inhibitors of the enzymes involved in the post-translational modifications of RAS [4].
The molecular development of NSCLC is initiated by the activation of oncogenes or the inactivation of tumor suppressor genes. Mutation of KRAS gene in lung cancer is more frequent than NRAS and HRAS and is often associated with poor prognosis and worse therapeutic outcome. Lung adenocarcinoma, the most common histological subtype of non-small-cell lung cancer (NSCLC), often carries a KRAS mutation with 20–50% frequency, followed by squamous cell carcinoma, subtype of NSCLC [3].
The present study was designed to determine the potential significance and the clinical relevance of two RAS gene family isoforms (KRAS and HRAS) and their mRNA expression levels in the group of non-small-cell lung cancer patients. Majority of previous scientific findings have focused on the mutation profiles of NSCLC patients or evaluation genes expression in lung cancer tissue. This research was aimed at analysing the relative levels of KRAS and HRAS genes mRNA expression in whole blood samples, which is an innovative approach, at three points of time during the patients' observation.