Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies

Miao Xu, Wei Long Zhang, Qing Zhu, Shanshan Zhang, You yuan Yao, Tong Xiang, Qi Sheng Feng, Zhe Zhang, Rou Jun Peng, Wei Hua Jia, Gui Ping He, Lin Feng, Zhao Lei Zeng, Bing Luo, Rui Hua Xu, Mu Sheng Zeng, Wei Li Zhao, Sai Juan Chen, Yi Xin Zeng, Yuchen Jiao

    Research output: Contribution to journalArticlepeer-review

    44 Scopus citations

    Abstract

    Rationale: Epstein-Barr virus (EBV) is associated with multiple malignancies with expression of viral oncogenic proteins and chronic inflammation as major mechanisms contributing to tumor development. A less well-studied mechanism is the integration of EBV into the human genome possibly at sites which may disrupt gene expression or genome stability. Methods: We sequenced tumor DNA to profile the EBV sequences by hybridization-based enrichment. Bioinformatic analysis was used to detect the breakpoints of EBV integrations in the genome of cancer cells. Results: We identified 197 breakpoints in nasopharyngeal carcinomas and other EBV-associated malignancies. EBV integrations were enriched at vulnerable regions of the human genome and were close to tumor suppressor and inflammation-related genes. We found that EBV integrations into the introns could decrease the expression of the inflammation-related genes, TNFAIP3, PARK2, and CDK15, in NPC tumors. In the EBV genome, the breakpoints were frequently at oriP or terminal repeats. These breakpoints were surrounded by microhomology sequences, consistent with a mechanism for integration involving viral genome replication and microhomology-mediated recombination. Conclusion: Our finding provides insight into the potential of EBV integration as an additional mechanism mediating tumorigenesis in EBV associated malignancies.

    Original languageEnglish (US)
    Pages (from-to)1115-1124
    Number of pages10
    JournalTheranostics
    Volume9
    Issue number4
    DOIs
    StatePublished - 2019

    Keywords

    • DNA integration
    • Epstein-Barr virus (EBV)
    • Nasopharyngeal carcinoma (NPC)

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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