METHYLATION OF TUMOR SUPPRESSOR GENES IN BENIGN AND MALIGNANT SALIVARY GLAND TUMORS: A SYSTEMATIC REVIEW AND META-ANALYSIS

The aim of the present systematic review was to critically analyze the relationship of tumor suppressor gene (TSGs) promoter methylation, a potent mechanism of gene silencing, and the development of salivary gland tumors, as well as the possible effect on clinical/histological characteristics. Review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (registration ID CRD42020218511). A comprehensive search of Web of Science, Scopus, PubMed and Cochrane Central Register of Controlled Trials was performed utilizing relevant key terms, supplemented by a search of gray literature. Newcastle-Ottawa Quality Assessment Scale (NOQAS) was used for the quality assessment of included studies. Sixteen cross-sectional and twelve case-control studies were included in the review, predominantly dealing with methylation in TSGs related to DNA repair, cell cycle and cell growth regulation and differentiation. Quantitative synthesis could be performed on P16 (inhibitor of cyclin-dependent kinase 4a), RASSF1A (Ras association domain family 1 isoform A) and MGMT (O6-methylguanine DNA methyltransferase) genes only. It showed that P16 and RASSF1A genes were more frequently methylated in salivary gland tumors compared to controls (<i>P</i> = .0002 and <i>P</i> &lt; .0001, respectively), while no significant difference was observed for MGMT. Additionally, P16 did not appear to be related to malignant transformation of pleomorphic adenomas (<i>P</i> = .330). In conclusion, TSG methylation is involved in salivary gland tumor pathogenesis and several genes might play a considerable role. Further studies are needed for a better understanding of complex epigenetic deregulation during salivary gland tumor development and progression.