Liu Ying, Yang Wenjun, Pan Yaqi, Ji Jiafu, Lu Zheming, Ke Yang
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital and Institute, Haidian, Beijing, China.
Key Laboratory of Reproduction and Heredity of Ningxia Region, Medical Oncology Department of General Hospital, Ningxia Medical University, Yinchuan, Ningxia, China.
Oncotarget. 2016 Jan 26;7(4):4903-14. doi: 10.18632/oncotarget.6751.
Epstein-Barr virus (EBV) is linked to the development of a variety of malignancies, including EBV-associated gastric carcinoma (EBVaGC). In this study, EBVaGC was detected in 15 (7.3%) of 206 GC cases. To identify the EBV genomic variation, EBV genomic sequences isolated from 9 EBVaGC biopsy specimens were successfully retrieved, designated EBVaGC1 to EBVaGC9. By comparative analysis of these strains with another 6 completely sequenced EBV strains, EBV-wild type, B95-8, AG876, GD1, GD2, and HKNPC1, it was demonstrated that EBVaGC1 to 9 were most closely related to the GD1 strain. Phylogenetic analysis of the GC biopsy specimen-derived EBV (GC-EBV) genomes was subsequently performed to assess their genomic diversity and it exhibited the greatest divergence from the type 2 strain, AG876. Compared with the reference EBV strain GD1, they harbored 961 variations in total, including 919 substitutions, 23 insertions, and 19 deletions. Single nucleotide polymorphism (SNP) density varied substantially across all known open reading frames and was highest in latency-associated genes. Moreover, we identified 2 interstrain recombinants at the EBNA1 locus, which provided a further mechanism for the generation of diversity. Some T-cell epitope sequences in EBNA1 and LMP2A genes showed extensive variation across strains, which implied their importance in the development of vaccines and T-cell therapy. In conclusion, we reported the first genome-wide view of sequence variation of EBV isolated from primary EBVaGC biopsy specimens, which might serve as an effective method for further understanding the genomic variations contribute to EBVaGC carcinogenesis and treatment.
爱泼斯坦-巴尔病毒（EBV）与多种恶性肿瘤的发生有关，包括EBV相关胃癌（EBVaGC）。在本研究中，206例胃癌病例中有15例（7.3%）检测到EBVaGC。为了鉴定EBV基因组变异，成功获取了从9例EBVaGC活检标本中分离的EBV基因组序列，命名为EBVaGC1至EBVaGC9。通过将这些菌株与另外6株全序列EBV菌株（EBV野生型、B95-8、AG876、GD1、GD2和HKNPC1）进行比较分析，结果表明EBVaGC1至9与GD1菌株关系最为密切。随后对胃癌活检标本来源的EBV（GC-EBV）基因组进行系统发育分析以评估其基因组多样性，结果显示其与2型菌株AG876的差异最大。与参考EBV菌株GD1相比，它们总共存在961个变异，包括919个替换、23个插入和19个缺失。单核苷酸多态性（SNP）密度在所有已知开放阅读框中差异很大，在潜伏相关基因中最高。此外，我们在EBNA1位点鉴定出2个株间重组体，这为多样性的产生提供了进一步的机制。EBNA1和LMP2A基因中的一些T细胞表位序列在不同菌株间显示出广泛变异，这暗示了它们在疫苗开发和T细胞治疗中的重要性。总之，我们报道了从原发性EBVaGC活检标本中分离的EBV序列变异的首个全基因组视图，这可能是进一步了解基因组变异对EBVaGC致癌作用和治疗贡献的有效方法。
