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Objective: To study the differences of histone gene methylome between normal and malignant head and neck cancers.Methods: We had profiles DNA methylation of 10 normal/cancer pairs of head and neck cancer by using Illuminia M450 CpG island array.Results: Three major findings were in this project.(1) The CpG sites of histone genes are hypermethylated in head and neck tumors.Particularly, HIST3H2A and HIST3H2BB are hypermethylated in all of the three samples of head and cancer (2) The tumor tissues shows global hyper-methylation of CpG sites in promoter/CpG island of many genes (3) Gene ontology analysis shows these hypermethylated genes are involved in transcription regulation (83 genes), signal transduction (59 genes), cell to cell signaling (36 genes) and cell-fate commitment (19genes).Conclusions: These candidate genes can serve as a biomarker for head and neck cancers through screening robust clinical samples.In addition, these candidate genes can provide precious information for further study of the epigenetic regulation of these candidate genes and the mechanisms involved in the tumorigenesis of the head and neck cancer.