Borozan Ivan, Zapatka Marc, Frappier Lori, Ferretti Vincent
Ontario Institute for Cancer Research, Toronto, Canada
German Cancer Research Center, Heidelberg, Germany.
J Virol. 2018 Jan 2;92(2). doi: 10.1128/JVI.01239-17. Print 2018 Jan 15.
Epstein-Barr virus (EBV) is a causative agent of a variety of lymphomas, nasopharyngeal carcinoma (NPC), and ∼9% of gastric carcinomas (GCs). An important question is whether particular EBV variants are more oncogenic than others, but conclusions are currently hampered by the lack of sequenced EBV genomes. Here, we contribute to this question by mining whole-genome sequences of 201 GCs to identify 13 EBV-positive GCs and by assembling 13 new EBV genome sequences, almost doubling the number of available GC-derived EBV genome sequences and providing the first non-Asian EBV genome sequences from GC. Whole-genome sequence comparisons of all EBV isolates sequenced to date (85 from tumors and 57 from healthy individuals) showed that most GC and NPC EBV isolates were closely related although American Caucasian GC samples were more distant, suggesting a geographical component. However, EBV GC isolates were found to contain some consistent changes in protein sequences regardless of geographical origin. In addition, transcriptome data available for eight of the EBV-positive GCs were analyzed to determine which EBV genes are expressed in GC. In addition to the expected latency proteins (EBNA1, LMP1, and LMP2A), specific subsets of lytic genes were consistently expressed that did not reflect a typical lytic or abortive lytic infection, suggesting a novel mechanism of EBV gene regulation in the context of GC. These results are consistent with a model in which a combination of specific latent and lytic EBV proteins promotes tumorigenesis. Epstein-Barr virus (EBV) is a widespread virus that causes cancer, including gastric carcinoma (GC), in a small subset of individuals. An important question is whether particular EBV variants are more cancer associated than others, but more EBV sequences are required to address this question. Here, we have generated 13 new EBV genome sequences from GC, almost doubling the number of EBV sequences from GC isolates and providing the first EBV sequences from non-Asian GC. We further identify sequence changes in some EBV proteins common to GC isolates. In addition, gene expression analysis of eight of the EBV-positive GCs showed consistent expression of both the expected latency proteins and a subset of lytic proteins that was not consistent with typical lytic or abortive lytic expression. These results suggest that novel mechanisms activate expression of some EBV lytic proteins and that their expression may contribute to oncogenesis.
爱泼斯坦-巴尔病毒（EBV）是多种淋巴瘤、鼻咽癌（NPC）以及约9%的胃癌（GC）的致病因子。一个重要问题是特定的EBV变体是否比其他变体更具致癌性，但目前由于缺乏EBV基因组测序，结论受到阻碍。在此，我们通过挖掘201例胃癌的全基因组序列以鉴定出13例EBV阳性胃癌，并组装13条新的EBV基因组序列，使可用的源自胃癌的EBV基因组序列数量几乎翻倍，且提供了首批源自非亚洲胃癌的EBV基因组序列，从而为这个问题提供了研究依据。对迄今测序的所有EBV分离株（85株来自肿瘤，57株来自健康个体）进行全基因组序列比较，结果显示尽管美国白种人胃癌样本的EBV分离株亲缘关系较远，但大多数胃癌和鼻咽癌的EBV分离株密切相关，这表明存在地域因素。然而，无论地域来源如何，EBV胃癌分离株在蛋白质序列上都存在一些一致的变化。此外，对8例EBV阳性胃癌的转录组数据进行分析，以确定哪些EBV基因在胃癌中表达。除了预期的潜伏蛋白（EBNA1、LMP1和LMP2A）外，还持续表达了特定的裂解基因子集，这并不反映典型的裂解或流产裂解感染，提示在胃癌背景下EBV基因调控存在新机制。这些结果与一种模型相符，即特定的潜伏性和裂解性EBV蛋白共同作用促进肿瘤发生。爱泼斯坦-巴尔病毒（EBV）是一种广泛传播的病毒，在一小部分个体中会引发癌症，包括胃癌（GC）。一个重要问题是特定的EBV变体是否比其他变体与癌症的关联性更强，但需要更多的EBV序列来解决这个问题。在此，我们从胃癌中生成了13条新的EBV基因组序列，使源自胃癌分离株的EBV序列数量几乎翻倍，并提供了首批源自非亚洲胃癌的EBV序列。我们进一步鉴定出胃癌分离株中一些EBV蛋白的序列变化。此外，对8例EBV阳性胃癌的基因表达分析显示，预期的潜伏蛋白和一部分裂解蛋白均持续表达，这与典型的裂解或流产裂解表达不一致。这些结果表明，新机制激活了一些EBV裂解蛋白的表达，且它们的表达可能有助于肿瘤发生。
