APOBEC-mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV-positive gastric cancer
APOBEC-mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV-positive gastric cancer
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DOI：
10.1002/ijc.32411
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发表时间：
2020-01-01
影响因子：
6.4
通讯作者：
da Silva, Israel T.
中科院分区：
文献类型：
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作者：
Bobrovnitchaia, Irina;Valieris, Renan;da Silva, Israel T.
病毒肿瘤发生的机制是多种多样的，包括受感染细胞表达的酶的脱靶活性，这些酶进化为靶向病毒基因组以控制其感染。在这些酶中，APOBECs的单链DNA编辑能力代表了一种保守的病毒感染反应，也可能导致宿主DNA的不良突变。在评估了240个胃癌样本的体细胞单核苷酸变异和转录组数据后，我们发现，在EBV+肿瘤中，APOBEC3s mrna表达和apobecs突变特征呈正相关，两者都增加了。通过观察APOBEC突变优先发生在最活跃转录本的基因组位点，这种相关性得到了加强。在112例胃癌患者的验证队列中证实了EBV感染和APOBEC3突变特征轴。我们的研究结果表明，APOBEC3在EBV+癌症中的上调可能会增加突变负荷，为EBV诱导胃癌发生的机制提供了进一步的线索。经过进一步验证，EBV- apobec轴可能是EBV+胃肿瘤突变进化的次要驱动力，其预后和治疗意义有待进一步研究。
Mechanisms of viral oncogenesis are diverse and include the off-target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single-strand DNA editing capability of APOBECs represent a well-conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single-nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA-expression and the APOBEC-mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation-signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV-induced gastric carcinogenesis. After further validation, this EBV-APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.