EVALUATION OF METHYLATION PROFILES OF AN
EPIDERMAL GROWTH FACTOR RECEPTOR GENE
IN A HEAD AND NECK SQUAMOUS CELL
CARCINOMA PATIENT GROUP
Mutlu M, Mutlu P, Azarkan S, Bayır O, Ocal B, Saylam G, Korkmaz MH
*Corresponding Author: Associate Professor Murad Mutlu, M.D., Department of Otorhinolaringology,
Health Sciences University, Ministry of Health, Dışkapı Yildirim Beyazit Training and Research Hopsital,
Sehit Ömer Halisdemir Street, No. 20, 06110, Dışkapı, Ankara, Turkey. Tel.: +90-312-516-2000.
Fax: +90-312-318-6690. E-mail: muradmutlu78@yahoo.com
page: 65
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INTRODUCTION
Head and neck cancers are defined as a group of malignant
diseases originating from the larynx, pharynx and oral
cavity. They have a high incidence, being classified as the
sixth most common cancer worldwide. On the other hand, if
they are not diagnosed at an early stage, they are associated
with high mortality rate [1]. The most frequently seen histological
type of head and neck cancers is the squamous cell
carcinoma (SCC), corresponding to approximately 90.0% of
cases [2]. Tobacco and alcohol consumption, viral infections
such as Epstein-Barr Virus and Human Papilloma Virus
(16/18), deficiencies of some vitamins and micronutrients,
are considered as promoting factors of this tumor type [3-5].
Various mutations, polymorphisms in oncogenes and
also epigenetic changes are responsible for development
and progression of head and neck squamous cell carcinoma
(HNSCC) [6]. In addition to these alterations, chromosomal
inversions, deletions, translocations, gains, losses
and trisomy of chromosome 7 are common in HNSCC
[7-9]. Differential gene expression patterns due to mutations
in several genes including tumor protein 53 (TP53),
cyclin-dependent kinase inhibitor 2A (CDKN2A), FAT
atypical cadherin 1 (FAT1), phosphatase and tensin homolog
(PTEN), HRas proto-oncogene, GTPase (HRAS),
phos-phatidylinositol-4,5-bisphosphate 3-kinase catalytic
subunit α (PIK3CA) and epidermal growth factor receptor
(EGFR) gene had been implicated in HNSCC [10,11]. Among these alterations, upregulation of the EGFR
gene has an important impact in the development of head
and neck cancers [12]. This receptor tyrosine kinase belongs
to ErbB family of cell surface receptors and is associated
with carcinogenesis due to its important regulation
role on multiple cell signaling pathways [12]. The
phos-phorylated receptor can activate mitogen-activated
protein kinase (MAPK), protein kinase B (Akt), extracellular
signal-regulated kinase (Erk), janus kinase/signal
transducers and activators of transcription (JAK/STAT)
pathways. The activation of these pathways result in cell
proliferation, apoptosis, angiogenesis, invasion and metastasis
[13]. Upregulation of the EGFR protein was seen in
approximately 90.0% HNSCC, however, amplification of
this gene locus was not prevalent being seen only in 10.0-
30.0% of cases [14]. This suggests that other mechanisms
rather than gene amplification may be associated with
EGFR overexpression.
In addition to nucleotide changes in the genome, epigenetic
alterations are the other group of events that cause
carcinogenesis. DNA and protein methylation profiles are
one of the most consistent epigenetic changes in human
cancers [15]. Cancer cells generally show a drastic change
in DNA methylation status, either exhibiting DNA hypomethylation,
which causes overexpression of oncogenes
or accompanying region-specific hypermethylation that
results in silencing of tumor suppressor genes [16-18].
Identification of DNA methylation patterns of specific
gene promoter regions can be used as biomarkers for early
diagnosis, classification, prognosis and therapy of human
cancers including HNSCC [19,20]. Tumor suppressor CDKN2A/
p16, cadherin 1 (CDH1), death associated protein
kinase 1 (DAPK) and O-6-methylguanine-DNA methyltransferase
(MGMT) genes were described as hypermethylated
in the larynx carcinoma, whereas the WNT signaling
pathway regulator (APC) and ubiquitin C-terminal hydrolase
L1 (UCHL1) were reported as hypermethylated in
nasopharyngeal carcinoma [21]. Hypermethylation in the
promoter region of semaphorin 3B (SEMA3B) was shown
in oral squamous cell carcinoma tissues [22]. On the other
hand, in HNSCC, hypermethylation correlates with the
stage of the disease and its potential to metastasis [23]. For
example, aberrant methylation of DAPK, netrin 1 receptor
(DCC) and MINT31 genes correlate with advanced stages
of the disease and metastasis [24,25].
The relationship between EGFR protein methylation
and HNSCC was shown in several studies. Saloura et al.
[26] stated that histone-lysine N-methyltransferase NSD3
(WHSC1L1) mediated methylation of EGFR protein resulted
in enhanced cell cycle progression via increasing
EGFR interaction with proliferating cell nuclear antigen
(PCNA) in HNSCC cells. In another study, the correlation
between the expression level of methyl-EGFR and protein
arginine N-methyltransferase 1 (PRMT1) was shown in
patients with head and neck cancer [27].
Although there are studies that show the association
between EGFR gene overexpression and EGFR protein
methylation status in HNSCC development, they are not
focused on EGFR gene promoter region methylation. The
reversibility of epigenetic changes by either reactivation
or suppression of epigenetically suppressed or activated
genes, is thought to be important for the development of
new treatment strategies in cancer treatment [28]. From
this point of view, in this study, we aimed to investigate the
methylation pattern of the promoter region of the EGFR
gene between Turkish HNSCC cancer patients and a control
group for the first time in order to identify the contribution
of this difference to the development and progression
of the disease.
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