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A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China.

ABSTRACT: Epstein-Barr virus (EBV), a widespread oncovirus, is associated with multiple cancers including nasopharyngeal carcinoma (NPC), gastric cancer and diverse lymphoid malignancies. Recent studies reveal that specific EBV strains or subtypes are associated with NPC development in endemic regions. However, these NPC specific subtypes were only identified in a portion of infected individuals due possibly to the limited samples size studied or the complicated population structures of the virus. To identify additional high-risk EBV subtypes, we conducted a comprehensive genetic analysis of 22 critical viral proteins by using the largest dataset of 628 EBV genomes and 792 sequences of single target genes/proteins from GenBank. The phylogenetic, principal component and genetic structure analyses of these viral proteins were performed through worldwide populations. In addition to the general Asia-Western/Africa geographic segregation, population structure analysis showed a 'Chinese-unique' cluster (96.57% isolates from China) was highly enriched in the NPC patients, compared to the healthy individuals (89.6% vs. 44.5%, P < 0.001). The newly identified EBV subtypes, which contains four Chinese-specific NPC-associated amino acid substitutions (BALF2 V317M, BNRF1 G696R, V1222I and RPMS1 D51E), showed a robust positive association with the risk of NPC in China (Odds Ratio = 4.80, 20.00, 18.24 and 32.00 for 1, 2, 3 and 4 substitutions, respectively, P _trend <0.001). Interestingly, the coincidence of positively selected sites with NPC-associated substitutions suggests that adaptive nonsynonymous mutation on critical proteins, such as BNRF1, may interact with host immune system and contribute to the carcinogenesis of NPC. Our findings provide a comprehensive overview of EBV genetic structure for worldwide populations and offer novel clues to EBV carcinogenesis from the aspect of evolution.

SUBMITTER: Xue WQ

PROVIDER: S-EPMC8458747 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China.

Xue Wen-Qiong WQ Wang Tong-Min TM Huang Jing-Wen JW Zhang Jiang-Bo JB He Yong-Qiao YQ Wu Zi-Yi ZY Liao Ying Y Yuan Lei-Lei LL Mu Jianbing J Jia Wei-Hua WH

Virus evolution 20210101 1

Epstein-Barr virus (EBV), a widespread oncovirus, is associated with multiple cancers including nasopharyngeal carcinoma (NPC), gastric cancer and diverse lymphoid malignancies. Recent studies reveal that specific EBV strains or subtypes are associated with NPC development in endemic regions. However, these NPC specific subtypes were only identified in a portion of infected individuals due possibly to the limited samples size studied or the complicated population structures of the virus. To iden ...[more]

PMID: 34567789

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Project description:BackgroundEpstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC).MethodsTo investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data.FindingsIn addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r2 = 0.55).InterpretationOur study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion.FundingThis study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL, General Research Fund (17103218 and 17102619) and seed funding for basic research (201611159158) to WD, and General Research Fund (17119618) to HC.

Dataset Information

A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China.

Publications

A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China.

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