title: A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma.
abstract: BACKGROUND
  Epstein-Barr virus (EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma (NPC), which has a high incidence in certain regions. This study aimed to address how EBV variations contribute to the risk of NPC.
  
  
  METHODS
  Using logistic regression analysis and based on the sequence variations at EBV-encoded RPMS1, a multi-stage association study was conducted to identify EBV variations associated with NPC risk. A protein degradation assay was performed to characterize the functional relevance of the RPMS1 variations.
  
  
  RESULTS
  Based on EBV-encoded RPMS1 variations, a single nucleotide polymorphism (SNP) in the EBV genome (locus 155391: G>A, named G155391A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China [P < 0.001, odds ratio (OR) = 4.47, 95% confidence interval (CI) 2.71-7.37]. The results were further validated in three independent cohorts from the NPC endemic region (P < 0.001, OR = 5.20, 95% CI 3.18-8.50 in 168 cases vs. 241 controls, and P < 0.001, OR = 5.27, 95% CI 4.06-6.85 in 726 cases vs. 880 controls) and a non-endemic region (P < 0.001, OR = 7.52, 95% CI 3.69-15.32 in 58 cases vs. 612 controls). The combined analysis in 1109 cases and 2052 controls revealed that the SNP G155391A was strongly associated with NPC (P(combined) < 0.001, OR = 5.27, 95% CI 4.31-6.44). Moreover, the frequency of the SNP G155391A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies. Furthermore, the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 protein.
  
  
  CONCLUSIONS
  Our study identified an EBV variation specifically and significantly associated with a high risk of NPC. These findings provide insights into the pathogenesis of NPC and strategies for prevention.
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. futuo_feng@163.com.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. futuo_feng@163.com.
authors.forename: Fu-Tuo
authors.initials: FT
authors.lastname: Feng
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. cuiqian@sysucc.org.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. cuiqian@sysucc.org.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. liuwsh@sysucc.org.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. liuwsh@sysucc.org.cn.
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Liu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. guoym@sysucc.org.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. guoym@sysucc.org.cn.
authors.forename: Yun-Miao
authors.initials: YM
authors.lastname: Guo
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. fengqsh@sysucc.org.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. fengqsh@sysucc.org.cn.
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Feng
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. chenlizh@sysucc.org.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. chenlizh@sysucc.org.cn.
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Chen
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. xumiao@sysucc.org.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. xumiao@sysucc.org.cn.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Medical Microbiology, Qingdao University Medical College, Qingdao, 266021, Shandong, P. R. China. qdluobing@163.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Luo
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. dajiang.li@hsc.utah.edu.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. dajiang.li@hsc.utah.edu.
authors.forename: Da-Jiang
authors.initials: DJ
authors.lastname: Li
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 17177, Stockholm, Sweden. Lifu.Hu@ki.se.
authors.forename: Li-Fu
authors.initials: LF
authors.lastname: Hu
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, 1007 MB, The Netherlands. j.middeldorp@vumc.nl.
authors.forename: Jaap M
authors.initials: JM
authors.lastname: Middeldorp
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, 1007 MB, The Netherlands. o.ramayanti@vumc.nl.
authors.forename: Octavia
authors.initials: O
authors.lastname: Ramayanti
authors.affiliation: Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, 999077, P. R. China. qtao@cuhk.edu.hk.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. caosm@sysucc.org.cn.|Department of Epidemiology, Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. caosm@sysucc.org.cn.
authors.forename: Su-Mei
authors.initials: SM
authors.lastname: Cao
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. jiaweih@mail.sysu.edu.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. jiaweih@mail.sysu.edu.cn.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Jia
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. beijx@sysucc.org.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. beijx@sysucc.org.cn.
authors.forename: Jin-Xin
authors.initials: JX
authors.lastname: Bei
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. zengyx@sysucc.org.cn.|Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. zengyx@sysucc.org.cn.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000453:epidemiology / Q000821:virology*; D005260:Female; D056726:Genetic Association Studies; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000453:epidemiology / Q000821:virology*; D009363:Neoplasm Proteins / Q000235:genetics*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment / Q000379:methods; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins; C423082:RPMS protein, Human herpesvirus 4; D014764:Viral Proteins