Epstein-Barr virus(EBV)is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma(NPC)and^10%of gastric cancer(GC)worldwide.Increasing evidence shows that acquired genetic and epigenetic ...Epstein-Barr virus(EBV)is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma(NPC)and^10%of gastric cancer(GC)worldwide.Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC.However,even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC(EBVa GC),suggesting a predominant role of epigenetic abnormities,especially promoter Cp G methylation,in the pathogenesis of NPC and EBVa GC.High frequencies of promoter methylation of tumor suppressor genes(TSGs)have been frequently reported in NPC and EBVa GC,with several EBV-induced methylated TSGs identified.Further characterization of the epigenomes(genome-wide Cp G methylation profile—methylome)of NPC and EBVa GC shows that these EBV-associated tumors display a unique high Cp G methylation epigenotype with more extensive gene methylation accumulation,indicating that EBV acts as a direct epigenetic driver for these cancers.Mechanistically,oncogenic modulation of cellular Cp G methylation machinery,such as DNA methyltransferases(DNMTs),by EBV-encoded viral proteins accounts for the EBV-induced high Cp G methylation epigenotype in NPC and EBVa GC.Thus,uncovering the EBV-associated unique epigenotype of NPC and EBVa GC would provide new insight into the molecular pathogenesis of these unique EBVassociated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.展开更多
基金Supported by grants from Health and Medical Research Fund(HMRF)(No.13120082)Hong Kong Research Grants Council(RGC)(No.474710 and T12-401/13R)+1 种基金National Natural Science Foundation of China(NSFC)(No.81372898 and 81172582)The Chinese University of Hong Kong
文摘Epstein-Barr virus(EBV)is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma(NPC)and^10%of gastric cancer(GC)worldwide.Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC.However,even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC(EBVa GC),suggesting a predominant role of epigenetic abnormities,especially promoter Cp G methylation,in the pathogenesis of NPC and EBVa GC.High frequencies of promoter methylation of tumor suppressor genes(TSGs)have been frequently reported in NPC and EBVa GC,with several EBV-induced methylated TSGs identified.Further characterization of the epigenomes(genome-wide Cp G methylation profile—methylome)of NPC and EBVa GC shows that these EBV-associated tumors display a unique high Cp G methylation epigenotype with more extensive gene methylation accumulation,indicating that EBV acts as a direct epigenetic driver for these cancers.Mechanistically,oncogenic modulation of cellular Cp G methylation machinery,such as DNA methyltransferases(DNMTs),by EBV-encoded viral proteins accounts for the EBV-induced high Cp G methylation epigenotype in NPC and EBVa GC.Thus,uncovering the EBV-associated unique epigenotype of NPC and EBVa GC would provide new insight into the molecular pathogenesis of these unique EBVassociated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.
