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

DISCUSSION

Gastrointestinal stromal tumors gained particular interest over the last decade as they are the most common mes-enchymal neoplasm in the GI tract, accounting for ~1.0% of all GI tumors, and are resistant to conventional chemotherapy and radiotherapy options [6,18]. In the era of precision medicine, discovery of particular molecular aberrations in GISTs promised novel treatment options applicable to the patients. Most GISTs were found to have activating mutations in two closely related tyrosine kinase receptors, KIT and PDGFRA. When they are mutated, the receptors become constitutively active and trigger uncontrolled cell proliferation leading to tumor formation. Therefore, use of specific tyrosine kinase inhibitors such as imatinib mesylate, restores normal signaling and was proved useful in the treatment of GISTs [18]. Discovery of such molecular markers and targeted treatments help to reduce the time consumed for diagnosis and decision of treatment method, improving survival times of patients. In this context, different alterations in the EGFR gene have also been used as a molecular marker for various tumor types, allowing the use of kinase inhibitors as effective treatment strategies in patients. The EGFR gene can gain oncogenic activity through structural rearrangements, gene amplifications and activating point mutations [19]. Point mutations generally cluster in the region that codes for the tyrosine kinase domain (exons 18-21) of the receptor, which results in constitutive activation of the encoded EGFR even in the absence of its ligand, resulting in excessive cell growth and proliferation leading to tumorigenesis [12]. In colorectal cancers, the EGFR gene copy number was shown to be high compared to normal tissue, somatic mutations affecting the kinase domain of the protein was seen frequently in NSCLC [20]. In gastric cancers, overexpression of the gene was well described, however, clinical trials targeting EGFR mostly returned disappointing results, probably because the patient selection procedure was not biomarker-assisted [12,21]. Additionally, aberrations in EGFR are frequent in other tumors including breast, brain and ovary. Use of anti-EGFR monoclonal antibodies or EGFR-targeted tyrosine kinase inhibitors is proven to be successful in these tumors. In addition to its specificity, TKIs in general are administrated orally and provide a rapid tumor response, unlike conventional cytotoxic chemotherapy options [22]. In this study, EGFR status of 40 somatic GIST samples derived from stromal mesenchymal origins were analyzed to understand whether any EGFR aberrations are present in GISTs to be potentially used in diagnosis and treatment of these tumors. Despite previous studies [20,22,23] that showed no significant association between EGFR expression and prognostic analysis of GISTs, a study by Shi et al. [24] indicated that only a small percentage of GISTs carry somatic EGFR mutations but speculated that it may play a role in the development and progression of the GISTs. However, the literature about the EGFR status in GISTs is still very limited. In the present study. The GIST samples were tested for therapy-targeted somatic EGFR mutations that are found in many cancer types (such as lung, breast, etc.) in the kinase domain region by targeted sequencing, and immunohistochemistry was also used for detection of any overexpression of the EGFR at the protein level. Data analyses indicated no mutations and no overexpression in the samples tested. The results explain that EGFR mutations potentially left out from primarily GISTs tumors. Therefore, these EGFR mutation-free GISTs have likely been resistant to TKI therapies. On the other hand, Apicella et al. [25] indicated that EGFR cannot be totally ignored as a potential target in gastric cancer, the EGFR pathway function should be examined for each subject considering the inhibition of the EGFR. According to another study [26], a phosphorylation of the EGFR pY1068 type was observed in the chromosomal instability as well as EGFR mutations, which vascular endothelial growth factor receptor 2 (VEGFR) targeted antibodies were recommended to gastric cancer patients. The main limitation of our study was the sample size. The study requires more patient samples and clinical data to support somatic EGFR mutations as serving as a prognostic biomarker for clinical decision making in GISTs. Moreover, we have only examined known driver mutations, which respond to treatment in other cancer types such as lung cancer. In the future study, full coding gene region sequencing analysis of the EGFR gene can be designed. Overall, supporting the previous study by Shi et al. [24], our results indicate that somatic EGFR mutations are rare in GISTs. Despite a bigger sample size being needed to confirm this conclusion [27], these primary data support that EGFR-tyrosine kinase inhibitor (TKI) treatment alone may not have impact on patients’ survival. However, it should be further investigated whether EGFR has a role in the initiation of these tumors. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Number 27 VOL. 27 (2), 2024	Number 27 VOL. 27 (1), 2024
Number 26 Number 26 VOL. 26(2), 2023 All in one	Number 26 VOL. 26(2), 2023
Number 26 VOL. 26, 2023 Supplement	Number 26 VOL. 26(1), 2023
Number 25 VOL. 25(2), 2022	Number 25 VOL. 25 (1), 2022
Number 24 VOL. 24(2), 2021	Number 24 VOL. 24(1), 2021
Number 23 VOL. 23(2), 2020	Number 22 VOL. 22(2), 2019
Number 22 VOL. 22(1), 2019	Number 22 VOL. 22, 2019 Supplement
Number 21 VOL. 21(2), 2018	Number 21 VOL. 21 (1), 2018
Number 21 VOL. 21, 2018 Supplement	Number 20 VOL. 20 (2), 2017
Number 20 VOL. 20 (1), 2017	Number 19 VOL. 19 (2), 2016
Number 19 VOL. 19 (1), 2016	Number 18 VOL. 18 (2), 2015
Number 18 VOL. 18 (1), 2015	Number 17 VOL. 17 (2), 2014
Number 17 VOL. 17 (1), 2014	Number 16 VOL. 16 (2), 2013
Number 16 VOL. 16 (1), 2013	Number 15 VOL. 15 (2), 2012
Number 15 VOL. 15, 2012 Supplement	Number 15 Vol. 15 (1), 2012
Number 14 14 - Vol. 14 (2), 2011	Number 14 The 9th Balkan Congress of Medical Genetics
Number 14 14 - Vol. 14 (1), 2011	Number 13 Vol. 13 (2), 2010
Number 13 Vol.13 (1), 2010	Number 12 Vol.12 (2), 2009
Number 12 Vol.12 (1), 2009	Number 11 Vol.11 (2),2008
Number 11 Vol.11 (1),2008	Number 10 Vol.10 (2), 2007
Number 10 10 (1),2007	Number 9 1&2, 2006
Number 9 3&4, 2006	Number 8 1&2, 2005
Number 8 3&4, 2004	Number 7 1&2, 2004
Number 6 3&4, 2003	Number 6 1&2, 2003
Number 5 3&4, 2002	Number 5 1&2, 2002
Number 4 Vol.3 (4), 2000	Number 4 Vol.2 (4), 1999
Number 4 Vol.1 (4), 1998	Number 4 3&4, 2001
Number 4 1&2, 2001	Number 3 Vol.3 (3), 2000
Number 3 Vol.2 (3), 1999	Number 3 Vol.1 (3), 1998
Number 2 Vol.3(2), 2000	Number 2 Vol.1 (2), 1998
Number 2 Vol.2 (2), 1999	Number 1 Vol.3 (1), 2000
Number 1 Vol.2 (1), 1999	Number 1 Vol.1 (1), 1998

About the journal ::: Editorial ::: Subscription ::: Information for authors ::: Contact