High risk Epstein-Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma
High risk Epstein-Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma
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DOI：
10.1002/ijc.32049
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发表时间：
2019-06-15
影响因子：
6.4
通讯作者：
Chiang, Alan Kwok Shing
中科院分区：
文献类型：
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作者：
Hui, Kwai Fung;Chan, Tsz Fung;Chiang, Alan Kwok Shing
EB病毒（Epstein-Barr virus，EBV）的某些变异体是否与鼻咽癌（nasopharyngeal carcinoma，NPC）的发病机制有关，目前尚无定论。我们进行了一项病例对照研究，比较从142名人口携带者的唾液样本中分离的EBV的基因组序列与来自62名香港NPC患者的原发性肿瘤活检标本。聚类分析发现人群携带者中存在1A ~ C和2A ~ B 5个亚群，而NPC中以1A和-B为主。全基因组关联研究（GWAS）在EBER基因座中鉴定了一组NPC相关的单核苷酸多态性（SNP）和indel。在香港96.8%的NPC病例和40.1%的人群携带者中发现的最显著的多态性是EBER 2下游的四个碱基缺失多态性（EBER-del），其位于坐标7188-7191（p = 1.91 × 10（-7））。此外，预测的EBER 2的二级结构改变，在几乎所有的NPC病例中具有可能的功能后果。使用与NPC相关的SNP和indel，为每个EBV变体分配遗传风险评分。具有高遗传风险评分的EBV变异在香港中国人中比其他地理区域的个体更普遍，在NPC中比其他EBV相关癌症更普遍。我们的结论是，高风险的EB病毒变异与多态性的EBER基因座，指定为HKNPC-EBERvar，与鼻咽癌密切相关。进一步研究这些新发现的多态性在NPC和其他EBV相关癌症中的生物学功能和潜在的临床应用是必要的。
Whether certain variants of Epstein-Barr virus (EBV) are linked to the pathogenesis of nasopharyngeal carcinoma (NPC), which shows a marked geographic restriction, remains an unresolved issue. We performed a case-control study comparing genomic sequences of EBV isolated from saliva samples of 142 population carriers with those from primary tumour biopsies derived from 62 patients with NPC of Hong Kong. Cluster analysis discovered five EBV subgroups 1A-C and 2A-B amongst the population carriers in contrast to the predominance of 1A and -B in the majority of NPC. Genome-wide association study (GWAS) identified a panel of NPC-associated single nucleotide polymorphisms (SNPs) and indels in the EBER locus. The most significant polymorphism, which can be found in 96.8% NPC cases and 40.1% population carriers of Hong Kong, is a four-base-deletion polymorphism downstream of EBER2 (EBER-del) from coordinates 7188-7191 (p = 1.91 x 10(-7)). In addition, the predicted secondary structure of EBER2 is altered with likely functional consequence in nearly all NPC cases. Using the SNPs and indels associated with NPC, genetic risk score is assigned for each EBV variant. EBV variants with high genetic risk score are found to be much more prevalent in Hong Kong Chinese than individuals of other geographic regions and in NPC than other EBV-associated cancers. We conclude that high risk EBV variants with polymorphisms in the EBER locus, designated as HKNPC-EBERvar, are strongly associated with NPC. Further investigation of the biological function and potential clinical application of these newly identified polymorphisms in NPC and other EBV-associated cancers is warranted.