Herein we provide a concise review of the state of methylation research as it pertains to clinical oral cancerous and precancerous tissues. We provide context for ongoing research efforts in this field and describe technologies that are presently being applied to analyze clinical specimens. We also discuss the various recurrent methylation changes that have been reported for oral malignancy (including those genes frequently silenced by promoter methylation and the small RNAs with activity modulated by methylation changes) and describe surrogate disease markers identified via epigenetic analysis of saliva and blood specimens from patients with oral cancer. 1. Background Oral cancer remains a major global killer [1]. Its entrenched poor survival rates make essential the ongoing molecular evaluation of oral cancers and precancers for the purpose of uncovering new tools for detecting and treating this disease. As with most solid epithelial tumors, oral cancers develop through a series of histopathological stages; hyperplasia leads to various degrees of dysplasia, which are followed by carcinoma in situ and finally invasive disease stages. The accumulation of various genetic and epigenetic alterations is understood to drive this progression paradigm. Herein we will discuss the role of DNA methylation in clinical oral tumorigenesis, focusing specifically on oral squamous cell carcinomas (OSCCs). DNA methylation occurs most frequently at cytosine residues of CpG dinucleotides in gene promoter regions, and much less frequently, within a gene [2]. CpG islands (CpG-rich regions spanning >500？bp with >55% GC content) exist in approximately 60–70% of promoters in the human genome [2, 3]. Methylation in the promoter region of a given gene can serve to decrease expression of that gene. This is thought to occur by either physically inhibiting the binding of proteins essential for transcription, or by recruiting proteins that have transcription repressive properties [4]. This reversible process helps govern gene expression activity in individual cells and is commonly disrupted in cancer, where gene silencing via methylation in particular can contribute to Knudsonian two-hit disruption of tumor suppressor genes [5]. Further, global hypomethylation of genes is understood to serve as a mechanism of oncogene activation, providing another avenue for methylation changes to contribute to tumorigenesis. In addition to being identified as an early event in tumorigenesis for many epithelial cancers, aberrant methylation has also been identified in dysplasia—and tumor—adjacent
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