Balkan Journal of Medical Genetics

MUTATION STATUS AND IMMUNOHISTOCHEMICAL CORRELATION OF EGFR MUTATIONS IN GASTROINTESTINAL STROMAL TUMORS
Ozkayalar H1, Ergoren MC2,3,*, Tuncel G2,3, Kurt S4, Cevik E4, Ozemri Sag S4, Yilmaz Ozguven B5, Kabukcuoglu F5, Mocan G1,2, Temel ŞG4,6,7,*
*Corresponding Author: Associate Professor Mahmut C. Ergoren, Department of Medical Genetics, Faculty of Medicine, Near East University, Near East Boulevard, 99138 Nicosia, Northern Cyprus. Tel.: +90-392-444-0535. Fax: +90-392-223-6461. E-mail: mahmucerkez.ergoren@neu.edu.tr. And/or: Associate Professor Sehime G. Temel, Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Özlüce Görüjke Kampüsü, 16059 Nilüfer, Bursa, Turkey. Tel.: +90-224-295-0000. Fax: +90-224-295-0019. E-mail: sehime@uludag.edu.tr.
page: 67

INTRODUCTION

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, generally occurring after the age of 50. A majority of all GISTs occur in the stomach (~60.0%), followed by the jejenum/ ileum, duodenum, rectum, appendix, colon and rarely, in the oesophagus [1]. Aggressive GISTs can me-tastasize to the liver and throughout the abdomen [2]. Patients frequently develop abdominal pain, nausea, fatigue and GI bleeding as the symptoms of GIST, while some remain asymptomatic [3]. Gastrointestinal stromal tumors are one of the leading causes of cancer deaths worldwide, therefore, understanding its molecular background and developing targeted therapy techniques are of high importance [4,5]. At the cellular level, GISTs are known to have a broad morphological spectrum. In general, they are divided into three histological subtypes: the spindle cell type being the most common, epithelioid type and rarely mixed spindle cell and epithelioid type [6]. In the last decade, investigation of alterations at the molecular level underlying the disease, greatly revolutionized both diagnosis and treatment strategies. The vast majority of GISTs were found to have activating mutations in the KIT receptor tyrosine kinase, which is accepted as a GIST biomarker by the European Group on Tumor Markers (EGTM). Currently, detection of CD117 (c-KIT) by immunohistochemistry is the method used for diagnosis or confirmation of imaging-based diagnoses [7]. Less frequently, mutations in the gene platelet-derived growth factor receptor α (PDGFRA) are detected in the KIT-negative GISTs [8-11]. On the other hand, expression or function of another well-known receptor tyrosine kinase, the epidermal growth factor receptor (EGFR) gene was found to be frequently altered in colorectal and gastric cancers as in many other tumor types [12,13]. The EGFR family comprises ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4 as well as the EGFR itself [14]. Binding of a ligand causes dimerization of receptors that leads to autophosphorylation of tyrosine residues, which then phosphorylates downstream signaling molecules triggering cellular pathways involved in DNA synthesis, cell growth, proliferation and differentiation [15]. Before the investigation of such molecular alterations and development of targeted treatments, complete surgical resection was the only potentially curative treatment of choice for localized GISTs [3]. However, use of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) as targeted therapy agents to inhibit carcinogenic actions of the tyrosine kinases in various human cancers, was shown to prolong overall survival and progression-free survival in cancers including GISTs, breast cancer, nonsmall cell lung cancer (NSCLC), and pancreatic cancers in the last decade [16]. Therefore, the importance of being able to detect mutations in cancer patients causing the disease and prescribing a therapy accordingly is clear. To the best of our knowledge, even though it is studied extensively in many tumor types, frequency of somatic EGFR mutations in GISTs has not been studied in the Turkish population before. In this study, mutation status of the EGFR gene and immu-nohistochemical marker changes in GISTs from 40 different Turkish patients was investigated to compare and correlate the mutation status with histopathological changes in the patient samples.

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