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

机译：通过针对爱泼斯坦-巴尔病毒相关恶性肿瘤的靶向测序，对爱泼斯坦-巴尔病毒整合的全基因组进行分析

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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.
机译：原理：爱泼斯坦-巴尔病毒（EBV）与多种恶性肿瘤相关，其表达的病毒致癌蛋白和慢性炎症是促成肿瘤发展的主要机制。尚未被充分研究的机制是EBV可能在可能破坏基因表达或基因组稳定性的位点整合到人类基因组中。方法：我们对肿瘤DNA进行测序，以通过基于杂交的富集分析EBV序列。使用生物信息学分析来检测癌细胞基因组中EBV整合的断裂点。结果：我们在鼻咽癌和其他与EBV相关的恶性肿瘤中确定了197个转折点。 EBV整合富集在人类基因组的脆弱区域，并且靠近肿瘤抑制基因和炎症相关基因。我们发现，EBV整合入内含子可以降低NPC肿瘤中炎症相关基因TNFAIP3，PARK2和CDK15的表达。在EBV基因组中，断点经常位于oriP或末端重复序列。这些断点被微同源序列包围，与涉及病毒基因组复制和微同源介导的重组的整合机制一致。结论：我们的发现为EBV整合作为介导EBV相关恶性肿瘤发生的另一种机制的潜力提供了见识。

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