Balkan Journal of Medical Genetics

DETECTING EGFR MUTATIONS IN PATIENTS WITH NON-SMALL CELL LUNG CANCER
Hammoudeh ZA, Antonova O, Staneva R, Nikolova D, Kyuchukov Y, Penev A, Mintchev T, Koleva V, Hadjidekova S, Toncheva D
*Corresponding Author: Zora A. Hammoudeh, Molecular Biologist, Department of Medical Genetics, Medical University Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria. Tel: +359-2-917-2735. Mobile: +359-88-943-0505. E-mail: zorahammoudeh@yahoo.com
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INTRODUCTION

In Bulgaria, lung cancer is a major health problem; it is more frequent in men than in women and most of the patients are diagnosed when they are in an advanced stage. Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer (85.0% of the cases) and it is the leading cause of death for male and female patients. As reported by the Bulgarian National Cancer Registry, NSCLC is the most common malignancy in men (19.1%) and the seventh in women (5.1%) [1,2]. Patients with NSCLC must be tested for prognostic markers associated with the survival of the patient and predictive biomarkers associated with the effect of the therapeutics. The target therapy contributes to the therapeutic approach according to specific genetic abnormalities in the tumor tissue. A lot of genes with predictive and prognostic significance in NSCLC are involved in the signaling pathway EGFR/ KRAS/RAF/ MEK/MEK/ERK [3]. The epidermal growth factor receptor (EGFR) gene encodes a protein that is a transmembrane glycoprotein, a member of the protein kinase family. The receptor for members of the EGFR family, has three domains: extracellular, trans membrane and intracellular. When the ligand is attached to the receptor a cascade is induced, tyrosine is autophosphorylated and the activity of tyrosine kinase is increased. The Ras/ Raf/MEK/ERK cascade transmits signals to transcription factors, which regulate gene expression and the activity of proteins involved in apoptosis. Mutations in the EGFR gene lead to over expression of the protein and had been associated with development of lung cancer, especially NSCLC. Sensitive mutations in the EGFR gene, such as mutations, deletions in exon 19, and the point mutation L858R in exon 21, have been reported in 80.0% of cases. They are found in 10.0-15.0% of the patients with adenocarcinomas and only 3.0% of other histological types. In advanced NSCLC, the presence of an activating mutation in EGFR gene confers better prognosis and predicts the sensitivity of tumor cells to EGFR tyrosine kinase inhibitors (TKIs) [4,5]. In Bulgaria, it is recommended that patients with adenocarcinoma be tested for the EGFR gene mutations, so they can be given EGFR TKI as a first-line therapy instead of chemotherapy. The mutations, deletion in exon 19 and L858R in exon 21 in the EGFR gene are associated with sensitivity to TKIs such as gefitinib [6]. Both mutations show increased sensitivity to first generation EGFR TKIs and they are the most frequent mutations in NSCLC [7]. Overall, mutations in the EGFR gene are more frequent in tumors classified as adenocarcinoma, in female patients who have never smoked. Therefore, those patients have the highest response rates to gefitinib [8,9]. Many molecular technologies are used in the diagnostic laboratories for the evaluation of the EGFR gene mutations. In this series of samples from Bulgarian NSCLC patients, we applied a real-time polymerase chain reaction (RT-PCR) analysis of DNA extracted from formalin-fixed paraffin-embedded tissue (FFPE). We present our data for the EGFR gene mutations, using RT-PCR kit (therascreen EGFR RGQ PCR kit) amplification refractory mutation system (ARMS) and Scorpions therascreen® EGFR test; Qiagen Ltd., Manchester, Greater Manchester, UK). The kit is optimized for in vitro diagnostics and detects the following mutations in the EGFR gene: exon 19 deletions, L858R, L861Q, G719X, S768I, exon 20 insertions, and the point mutation T790M.

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