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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DISCUSSION
The average 5-year survival in HNSCC patients is
approximately 60.0% and this ratio lowers with increasing
stages at diagnosis. This indicates a need for noninvasive
tests that facilitate the detection of early disease [30]. DNA
methylation is an early event in tumorigenesis of HNSCC,
thus, identification of methylation profiles of specific genes
can be used as biomarkers and provide great promise for
early detection and treatment in HNSCC [31]. Differences
in DNA methylation profiles in the CpG islands help us to
understand the pathogenesis of complex diseases including
cancer [32]. Methylation profiles not only show the differentiation
of normal cells to cancerous cells, but also help to define
specific cancer types [33]. In addition, epigenetic studies
provide margin assessment that can be helpful to surgeons
and doctors in clinics. In selected patients with HNSCC
requiring comprehensive resection, rapid molecular margin
analysis using MS-PCR, is feasible and may be performed
intraoperatively [34]. (Author: this sentence is not complete)
PAGE Frequent hypermethylation of tumor-related genes
were observed in oral squamous cell carcinoma (OSCC) and
HNSCC [35]. The genes found to be inactivated by DNA
methylation events are involved in the cell cycle control,
apoptosis, WNT signaling pathway and DNA repair mechanisms
[35]. A systematic search in databases for HNSCC
resulted in some reported genes that show hypermethylation
on their promoter region (ALDH3A1, CCNA1, CDH1, CDKN2A/
p16, CDKN2B/p15, DAPK, DCC, EDNRB, ERCC1,
ESR1, FANCC, FHIT, GALR1, GALR2, HIC1, HOTAIR,
KIF1A, LKB1, MGMT, MLH1, PTCH1, RARβ2, RASSF4,
RASSF5, RUNX3, SEMA3B, SPARC, TAP1, TCF21, TIMP3
and TRG) [36]. However, some of these potential epigenetic
biomarkers have not yet been clinically implemented [37].
In addition to these genes, EGFR had also been implicated
in HNSCC. Upregulation of the EGFR gene was
shown to be important in head and neck cancers due to
its important regulation role on multiple cell signaling
pathways [12]. The EGFR gene expression was seen both
in premalignant oral lesions and invasive HNSCC tumor
samples being unrelated to tumor stage [38]. Overproduction
of EGFR protein was commonly seen (approximately
90.0%) in HNSCC patients, whereas amplification of this
gene locus was not frequent (10.0-30.0%) [14]. In some
of the studies, the relationship between methylated EGFR
protein and HNSCC was shown [26,27]. However, none of
these studies focused on if the upregulation of the EGFR
gene can be a result of EGFR gene promoter region methylation
in HNSCC patients and can be a prediction marker
for the disease by comparing healthy individuals.
In our study, we aimed to consider the mechanisms of
overexpression of the EGFR gene in Turkish HNSCC patient
group rather than gene amplification. Thus, we focused
on methylation status of the EGFR gene promoter region
and wanted to contribute to the gene lists in the databases.
On the other hand, it is vital to determine non-invasive tests
from blood samples that facilitate the detection of early disease.
Studying DNA methylation profiles from peripheral
blood samples is an easy and noninvasive way. There have
been several recent reports on blood-based methylation
biomarkers for various solid tumor types including HNSCC
[30,39-42]. DNA methylation is amenable to measure and
readily available in peripheral blood. The results show most
likely EGFR methylation of white blood cells such as might
be observed in a specific immune response to the tumor
and of circulating tumor cells, if any. To the best of our
knowledge, the EGFR gene promoter methylation profile
for Turkish HNSCC patients has so far not been studied
in peripheral blood samples and compared with a healthy
control group, so the results of this study may contribute
to the literature.
According to clinicopathological data of the patients;
the methylation status of the EGFR gene promoter was not
found to be related to age, gender or tumor stage. Although
some publications in the literature suggest that different
methylation profiles vary, depending on age and gender for
various genes in different types of cancer and normal tissues
[43-45], no such difference was found to be statistically
significant for the EGFR gene in our HNSCC patient group.
In addition, methylation of the EGFR gene in the promoter
region was not associated with HNSCC development when
compared with the control group.
To the best of our knowledge, there are no studies in
the literature showing EGFR gene promoter methylation
status from blood samples of HNSCC patients and comparing
them with healthy individuals for the prediction of early
disease. The methylation status of EGFR CpG islands was
examined in a series of solid tumor types including head
and neck in the USA, and EGFR hypermethylation was detected
only in 35.0% of cases and not considered statistically
significant [46]. On the other hand, in our study, 79.0% of
Turkish HNSCC patients were found to be methylated. Although
in this study Montero et al. [46] used pyrosqeuencing
results of tumor samples, it is important to show the possible
relation between EGFR promoter methylation status and
HNSCC from other ethnic groups.
In conclusion, promoter methylation of specific genes
is emerging as one of the most promising cancer detection
strategies and to be a tumor-specific marker for early diagnosis
of HNSCC. The results of this study suggest that the
EGFR gene promoter methylation status is not associated
with HNSCC in the studied Turkish patient group. However,
in order to make a more definitive conclusion, it is necessary
to increase the number of cases and other target genes that
have important roles in the progression of HNSCC included
in our future studies.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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