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Introduction
Cervical cancer (CC) is the second most common type of cancer affecting the female population. The World Health Organization (WHO) and GLOBOCAN 2012 have recorded ~528,000 new cases of CC globally (1). The development of CC takes place over several years, and involves a precancerous stage known as cervical intraepithelial neoplasia (CIN), which is divided into three main stages (CIN1, CIN2, CIN3). The primary cause of this disease is infection by human papillomavirus (HPV). At present, over 100 types of HPV have been identified, of which the most prevalent types are HPV16/18, which are responsible for cervical carcinogenesis (2). According to the latest data the most common HPV virus identified in high-grade lesions is HPV16 (47.4%) followed by HPV31 (12.4%), HPV33 (7.1%) and HPV18 (7.1%) (3). The HPV genome is divided into three main regions; the long control region (LCR), which is composed of six open reading frames (ORFs); and the ‘late region’, with two ORFs coding for the viral structural proteins L1 and L2 (4). The major mechanism that engages HPV16/18 in cervical carcinogenesis is the manifestation of two early viral genes: E6 and E7 (known as viral oncogenes). E6 protein binds to the tumor suppressor gene p53 and causes its degradation while E7 inactivates the pRb gene. These mechanisms cause disruptions of cell cycle regulation (5).
Cytological screening has reduced the number of CC-associated mortalities; however, CC is still among the most prevalent oncological diseases, as many women underestimate the importance of regular gynecological examinations.
At present, classical cytology-based screening is being replaced in favor of diagnosing patients with high-risk HPV types, studies are also focused on additional co-factors, such as epigenetics and the search for suitable bio-markers identified via a triage test, PAP smear or HPV test. Epigenetic changes are stable alterations of gene expression without alteration in the DNA sequence itself, and can cause disease even in the absence of a mutation in the gene (6). These changes also include DNA methylation, which is characterized as a covalent chemical modification by the addition of a methylated group to the fifth carbon of the cytosine ring (5mC), thereby preventing access to proteins. DNA methylation is a typical mammalian cellular process and is one of the most well-established markers that defines a...