Abstract
Squamous cell carcinoma of the oral region (OSCC) is one of the most common and highly aggressive malignancies worldwide, despite the fact that significant results have been achieved during the last decades in its detection, prevention and treatment. Although many efforts have been made to define the molecular signatures that identify the clinical outcome of oral cancers, OSCC still lacks reliable prognostic molecular markers. Scientific evidence indicates that transition from normal epithelium to pre-malignancy, and finally to oral carcinoma, depends on the accumulation of genetic and epigenetic alterations in a multistep process. Unlike genetic alterations, epigenetic changes are heritable and potentially reversible. The most common examples of such changes are DNA methylation, histone modification, and small non-coding RNAs. Although several epigenetic changes have been currently linked to OSCC initiation and progression, they have been only partially characterized. Over the last decade, it has been demonstrated that especially aberrant DNA methylation plays a critical role in oral cancer. The major goal of the present paper is to review the recent literature about the epigenetic modifications contribution in early and later phases of OSCC malignant transformation; in particular we point out the current evidence of epigenetic marks as novel markers for early diagnosis and prognosis as well as potential therapeutic targets in oral cancer.
Highlights
Head and neck cancers constitute the sixth most common malignant tumors worldwide, affecting approximately 650,000 people and causing almost 350,000 cancer deaths per year [1,2]
A clear correlation between the epigenetic-driven deregulation of gene expression and the oral cancer progression is at present not fully demonstrated, hypermethylation and consequent silencing of several tumor suppressor genes, out of a group of more than 40 genes, has been identified in oral squamous cell carcinoma (OSCC) [20] (Table 2); the genes found hypermethylated in OSCC cover a wide range of cellular processes, including cell cycle control (p16, p15), apoptosis (p14, DAPK, p73 and RASSF1A), Wnt signalling (APC, WIF1, RUNX3), cell-cell adhesion (E-cadherin), and DNA-repair (MGMT and hMLH1) [30,31,32,33]
P53 shows a loss of function due to epigenetic events, instead of genetic alterations. This is the case of the epigenetic inactivation of p53 non mutated protein by the E6 protein of high-risk Human Papillomavirus (HPV), in OSCC as in some laryngeal cancers
Summary
Head and neck cancers constitute the sixth most common malignant tumors worldwide, affecting approximately 650,000 people and causing almost 350,000 cancer deaths per year [1,2]. The poor prognosis of OSCC is mainly due to a low response rate to current therapeutic strategies, for tumors diagnosed in advanced stage This specific subset of patients is characterized by a high occurrence of invasion to surrounding tissues, lymph node and distant metastasis and by a peculiarly high risk of second malignancy during the patient’s lifetime. The genetic alterations involved in the development and progression of oral premalignancy and OSCC, are caused by irreversible changes in DNA sequence including gene deletions, amplifications and mutations leading both to oncogenes activation or tumor suppressor genes inactivation [12,13]. Epigenetics is another major player in multistep carcinogenesis of oral cancers. We aim to highlight the important translational implications of the epigenetic regulation as new diagnostic, prognostic and predictive markers in oral cancer, an growing field of research due to the poor reliability of conventional markers in OSCC diagnosis, treatment and follow-up [12]
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