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Volume 103, Issue 3

Genomic landscape of Epstein–Barr virus in familial nasopharyngeal carcinoma No Access

Abstract

To better understand the genomic characteristics of Epstein–Barr virus (EBV) in familial nasopharyngeal carcinoma (NPC), we sequenced the EBV genomes by whole-genome capture in 38 unrelated patients with NPC family history in first-degree relatives and 47 healthy controls, including 13 with family history and 34 without. Compared with type 1 reference genome, mutation hotspots were observed in the latent gene regions of EBV in familial NPC cases. Population structure analysis showed that one cluster has a higher frequency in familial cases than in controls (OR=5.33, 95 % CI 2.50–11.33, =1.42×10), and similar population structure composition was observed among familial and sporadic NPC cases in high-endemic areas. By genome-wide association analysis, four variants were found to be significantly associated with familial NPC. Consistent results were observed in the meta-analysis integrating two published case-control EBV sequencing studies in NPC high-endemic areas. High-risk haplotypes of EBV composed of 34 variants were associated with familial NPC risk (OR=13.85, 95 % CI 4.13–46.44, =2.06×10), and higher frequency was observed in healthy blood-relative controls with NPC family history (9/13, 69.23 %) than those without family history (16/34, 47.06%). This study suggested the potential contribution of EBV high-risk subtypes to familial aggregation of NPC.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Epstein–Barr virus , familial aggregation , genetic variation and nasopharyngeal carcinoma
Funding
This study was supported by the:
  • Key Area Research and Development Program of Guangdong Province (Award 2019B110233004)
    • Principle Award Recipient: Xiao-HuiZheng
  • the Sino-Sweden Joint Research Program (Award 81861138006)
    • Principle Award Recipient: Wei-HuaJia
  • Science and Technology Planning Project of Guangdong Province (Award 2019B030316031)
    • Principle Award Recipient: Wei-HuaJia
  • the Science and Technology Planning Project of Guangzhou (Award 201904010467)
    • Principle Award Recipient: Xiao-HuiZheng
  • National Natural Science Foundation of China (Award 82003520)
    • Principle Award Recipient: Tong-MinWang
  • National Natural Science Foundation of China (Award 81903395)
    • Principle Award Recipient: Yong-QiaoHe
  • National Natural Science Foundation of China (Award 81802708)
    • Principle Award Recipient: Xiao-HuiZheng
  • National Natural Science Foundation of China (Award 81973131)
    • Principle Award Recipient: Wei-HuaJia
  • the Special Support Program for High-level Professionals on Scientific and Technological Innovation of Guangdong Province (Award 2014TX01R201)
    • Principle Award Recipient: Wei-HuaJia
  • Basic and Applied Basic Research Foundation of Guangdong Province (Award 2021B1515420007)
    • Principle Award Recipient: Wei-HuaJia
  • Natural Science Foundation of Guangdong Province (Award 2021A1515012397)
    • Principle Award Recipient: Jiang-BoZhang
© 2021 The Authors
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/content/journal/jgv/10.1099/jgv.0.001728
2022-03-29
2024-04-19
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References

  1. Chen Y-P, Chan ATC, Le Q-T, Blanchard P, Sun Y et al. Nasopharyngeal carcinoma. Lancet 2019; 394:64–80 [View Article] [PubMed]
     [Google Scholar]
  2. Liu Z, Chang ET, Liu Q, Cai Y, Zhang Z et al. Quantification of familial risk of nasopharyngeal carcinoma in a high-incidence area. Cancer 2017; 123:2716–2725 [View Article] [PubMed]
     [Google Scholar]
  3. Huang S-F, Hsiao J-H, Young C-K, Chien H-T, Kuo C-F et al. Familial aggregation of nasopharyngeal carcinoma in Taiwan. Oral Oncol 2017; 73:10–15 [View Article] [PubMed]
     [Google Scholar]
  4. Cao S-M, Chen S-H, Qian C-N, Liu Q, Xia Y-F. Familial nasopharyngeal carcinomas possess distinguished clinical characteristics in southern China. Chin J Cancer Res 2014; 26:543–549 [View Article] [PubMed]
     [Google Scholar]
  5. Feng B-J, Huang W, Shugart YY, Lee MK, Zhang F et al. Genome-wide scan for familial nasopharyngeal carcinoma reveals evidence of linkage to chromosome 4. Nat Genet 2002; 31:395–399 [View Article] [PubMed]
     [Google Scholar]
  6. Dai W, Zheng H, Cheung AKL, Tang CS, Ko JMY et al. Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma. Proc Natl Acad Sci U S A 2016; 113:3317–3322 [View Article] [PubMed]
     [Google Scholar]
  7. Yu GQ, Hsu WL, Coghill AE, Yu KJ, Wang CP, Lou PJ et al. Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma. Sci Rep 2019; 9:10
     [Google Scholar]
  8. Chen CJ, Liang KY, Chang YS, Wang YF, Hsieh T et al. Multiple risk factors of nasopharyngeal carcinoma: Epstein-Barr virus, malarial infection, cigarette smoking and familial tendency. Anticancer Res 1990; 10:547–553 [PubMed]
     [Google Scholar]
  9. Luo X-Y, Liu W-S, Chen L-Z, Feng Q-S, Zeng Y-X et al. Comparative study on risk factors and family history of familial and sporadic nasopharyngeal carcinoma patients. Zhonghua Yu Fang Yi Xue Za Zhi 2009; 43:293–298 [PubMed]
     [Google Scholar]
  10. Pickard A, Chen C-J, Diehl SR, Liu M-Y, Cheng Y-J et al. Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan. Int J Cancer 2004; 111:117–123 [View Article] [PubMed]
     [Google Scholar]
  11. Qin H-D, Jia W-H, Zhang L-L, Liu N, Zhou X-X et al. Elevated Epstein-Barr virus seroreactivity among unaffected members of families with nasopharyngeal carcinoma. J Med Virol 2011; 83:1792–1798 [View Article] [PubMed]
     [Google Scholar]
  12. Zheng M-Q, Wang T-M, Liao Y, Xue W-Q, He Y-Q et al. Nasopharyngeal Epstein-Barr virus DNA loads in high-risk nasopharyngeal carcinoma families: Familial aggregation and host heritability. J Med Virol 2020; 92:3717–3725 [View Article] [PubMed]
     [Google Scholar]
  13. Shen G-P, Pan Q-H, Hong M-H, Qin H-D, Xu Y-F et al. Human genetic variants of homologous recombination repair genes first found to be associated with Epstein-Barr virus antibody titers in healthy Cantonese. Int J Cancer 2011; 129:1459–1466 [View Article] [PubMed]
     [Google Scholar]
  14. Coghill AE, Hsu W-L, Yang Q, Wang C-P, Lou P-J et al. Elevated antibodies against Epstein-Barr virus among individuals predicted to carry nasopharyngeal carcinoma susceptibility variants. J Gen Virol 2018; 99:1268–1273 [View Article] [PubMed]
     [Google Scholar]
  15. Zhang J-B, Huang S-Y, Wang T-M, Dong S-Q, He Y-Q et al. Natural Variations in BRLF1 Promoter Contribute to the Elevated Reactivation Level of Epstein-Barr Virus in Endemic Areas of Nasopharyngeal Carcinoma. EBioMedicine 2018; 37:101–109 [View Article] [PubMed]
     [Google Scholar]
  16. Lieberman PM. Virology. Epstein-Barr virus turns 50. Science 2014; 343:1323–1325 [View Article] [PubMed]
     [Google Scholar]
  17. Palser AL, Grayson NE, White RE, Corton C, Correia S et al. Genome diversity of Epstein-Barr virus from multiple tumor types and normal infection. J Virol 2015; 89:5222–5237 [View Article] [PubMed]
     [Google Scholar]
  18. Yao Y, Xu M, Liang L, Zhang H, Xu R et al. Genome-wide analysis of Epstein-Barr virus identifies variants and genes associated with gastric carcinoma and population structure. Tumour Biol 2017; 39:1010428317714195 [View Article] [PubMed]
     [Google Scholar]
  19. Hui KF, Chan TF, Yang W, Shen JJ, Lam KP et al. High risk Epstein-Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma. Int J Cancer 2019; 144:3031–3042 [View Article] [PubMed]
     [Google Scholar]
  20. Peng R-J, Han B-W, Cai Q-Q, Zuo X-Y, Xia T et al. Genomic and transcriptomic landscapes of Epstein-Barr virus in extranodal natural killer T-cell lymphoma. Leukemia 2019; 33:1451–1462 [View Article] [PubMed]
     [Google Scholar]
  21. Xu M, Yao Y, Chen H, Zhang S, Cao S-M et al. Genome sequencing analysis identifies Epstein-Barr virus subtypes associated with high risk of nasopharyngeal carcinoma. Nat Genet 2019; 51:1131–1136 [View Article] [PubMed]
     [Google Scholar]
  22. Bristol JA, Djavadian R, Albright ER, Coleman CB, Ohashi M et al. A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection. PLoS Pathog 2018; 14:e1007179 [View Article] [PubMed]
     [Google Scholar]
  23. Church TM, Verma D, Thompson J, Swaminathan S. Efficient Translation of Epstein-Barr Virus (EBV) DNA Polymerase Contributes to the Enhanced Lytic Replication Phenotype of M81 EBV. J Virol 2018; 92:e01794-17 [View Article] [PubMed]
     [Google Scholar]
  24. Delecluse S, Poirey R, Zeier M, Schnitzler P, Behrends U et al. Identification and Cloning of a New Western Epstein-Barr Virus Strain That Efficiently Replicates in Primary B Cells. J Virol 2020; 94:10 [View Article] [PubMed]
     [Google Scholar]
  25. Wang F-W, Wu X-R, Liu W-J, Liang Y-J, Huang Y-F et al. The nucleotide polymorphisms within the Epstein-Barr virus C and Q promoters from nasopharyngeal carcinoma affect transcriptional activity in vitro. Eur Arch Otorhinolaryngol 2012; 269:931–938 [View Article] [PubMed]
     [Google Scholar]
  26. Lo YM, Chan LY, Lo KW, Leung SF, Zhang J et al. Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 1999; 59:1188–1191 [PubMed]
     [Google Scholar]
  27. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 2014; 30:2114–2120 [View Article] [PubMed]
     [Google Scholar]
  28. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods 2012; 9:357–359 [View Article] [PubMed]
     [Google Scholar]
  29. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009; 25:1754–1760 [View Article] [PubMed]
     [Google Scholar]
  30. Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 2010; 26:841–842 [View Article] [PubMed]
     [Google Scholar]
  31. Picard Toolkit GitHub Repository; 2019 http://broadinstitute.github.io/picard/
  32. Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics 2011; 27:2987–2993 [View Article] [PubMed]
     [Google Scholar]
  33. Zerbino DR, Birney E. Velvet: algorithms for de novo short read assembly using de Bruijn graphs. Genome Res 2008; 18:821–829 [View Article] [PubMed]
     [Google Scholar]
  34. Walker BJ, Abeel T, Shea T, Priest M, Abouelliel A et al. Pilon: an integrated tool for comprehensive microbial variant detection and genome assembly improvement. PLoS One 2014; 9:e112963 [View Article] [PubMed]
     [Google Scholar]
  35. Assefa S, Keane TM, Otto TD, Newbold C, Berriman M. ABACAS: algorithm-based automatic contiguation of assembled sequences. Bioinformatics 2009; 25:1968–1969 [View Article] [PubMed]
     [Google Scholar]
  36. Boetzer M, Pirovano W. Toward almost closed genomes with GapFiller. Genome Biol 2012; 13:R56 [View Article] [PubMed]
     [Google Scholar]
  37. Gurevich A, Saveliev V, Vyahhi N, Tesler G. QUAST: quality assessment tool for genome assemblies. Bioinformatics 2013; 29:1072–1075 [View Article] [PubMed]
     [Google Scholar]
  38. Li H. Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics 2018; 34:3094–3100 [View Article] [PubMed]
     [Google Scholar]
  39. Cingolani P, Platts A, Wang LL, Coon M, Nguyen T et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 2012; 6:80–92 [View Article] [PubMed]
     [Google Scholar]
  40. Yang Z. PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol 2007; 24:1586–1591 [View Article] [PubMed]
     [Google Scholar]
  41. Alexander DH, Novembre J, Lange K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res 2009; 19:1655–1664 [View Article] [PubMed]
     [Google Scholar]
  42. Francis RM. pophelper: an R package and web app to analyse and visualize population structure. Mol Ecol Resour 2017; 17:27–32 [View Article] [PubMed]
     [Google Scholar]
  43. Wegner F, Lassalle F, Depledge DP, Balloux F, Breuer J. Co-evolution of sites under immune selection shapes Epstein-Barr Virus population structure. Mol Biol Evol 2019msz152 [View Article] [PubMed]
     [Google Scholar]
  44. Xue W-Q, Wang T-M, Huang J-W, Zhang J-B, He Y-Q et al. A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. Virus Evol 2021; 7:veab010 [View Article] [PubMed]
     [Google Scholar]
  45. Zheng X, Levine D, Shen J, Gogarten SM, Laurie C et al. A high-performance computing toolset for relatedness and principal component analysis of SNP data. Bioinformatics 2012; 28:3326–3328 [View Article] [PubMed]
     [Google Scholar]
  46. Wickham H. ggplot2: Elegant Graphics for Data Analysis Springer-Verlag New York; 2016
     [Google Scholar]
  47. Nguyen L-T, Schmidt HA, von Haeseler A, Minh BQ. IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol 2015; 32:268–274 [View Article] [PubMed]
     [Google Scholar]
  48. Yu G, Lam T-Y, Zhu H, Guan Y. Two Methods for Mapping and Visualizing Associated Data on Phylogeny Using Ggtree. Mol Biol Evol 2018; 35:3041–3043 [View Article] [PubMed]
     [Google Scholar]
  49. Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet 2012; 44:821–824 [View Article] [PubMed]
     [Google Scholar]
  50. Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 2010; 42:436–440 [View Article] [PubMed]
     [Google Scholar]
  51. Collins C, Didelot X. A phylogenetic method to perform genome-wide association studies in microbes that accounts for population structure and recombination. PLoS Comput Biol 2018; 14:e1005958 [View Article] [PubMed]
     [Google Scholar]
  52. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002; 70:425–434 [View Article] [PubMed]
     [Google Scholar]
  53. Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD. The immunology of Epstein-Barr virus-induced disease. Annu Rev Immunol 2015; 33:787–821 [View Article] [PubMed]
     [Google Scholar]
  54. Vita R, Mahajan S, Overton JA, Dhanda SK, Martini S et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res 2019; 47:D339–D343 [View Article] [PubMed]
     [Google Scholar]
  55. Gonzalez-Galarza FF, McCabe A, Santos EJMD, Jones J, Takeshita L et al. Allele frequency net database (AFND) 2020 update: gold-standard data classification, open access genotype data and new query tools. Nucleic Acids Res 2020; 48:D783–D788 [View Article] [PubMed]
     [Google Scholar]
  56. Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 2019; 22:153–160 [View Article] [PubMed]
     [Google Scholar]
  57. Midgley RS, Bell AI, Yao QY, Croom-Carter D, Hislop AD et al. HLA-A11-restricted epitope polymorphism among Epstein-Barr virus strains in the highly HLA-A11-positive Chinese population: incidence and immunogenicity of variant epitope sequences. J Virol 2003; 77:11507–11516 [View Article] [PubMed]
     [Google Scholar]
  58. Wen-Qiong Xue T-M, Huang J-W, Zhang J-B, He Y-Q, Wu Z-Y et al. A comprehensive analysis of genetic diversity of EBV reveals potential highrisk subtypes associated with nasopharyngeal carcinoma in china. Virus Evol 2021; 7: veab010
    [Google Scholar]
  59. Duan Y, Li Z, Cheng S, Chen Y, Zhang L et al. Nasopharyngeal carcinoma progression is mediated by EBER-triggered inflammation via the RIG-I pathway. Cancer Lett 2015; 361:67–74 [View Article] [PubMed]
     [Google Scholar]
  60. Lam WKJ, Ji L, Tse OYO, Cheng SH, Jiang P et al. Sequencing Analysis of Plasma Epstein-Barr Virus DNA Reveals Nasopharyngeal Carcinoma-Associated Single Nucleotide Variant Profiles. Clin Chem 2020; 66:598–605 [View Article] [PubMed]
     [Google Scholar]
  61. Rühl J, Leung CS, Münz C. Vaccination against the Epstein-Barr virus. Cell Mol Life Sci 2020; 77:4315–4324 [View Article] [PubMed]
     [Google Scholar]
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Genomic landscape of Epstein–Barr virus in familial nasopharyngeal carcinoma
J. Gen. Virol. 103, 001728 (2022); https://doi.org/10.1099/jgv.0.001728
/content/journal/jgv/10.1099/jgv.0.001728
/content/journal/jgv/10.1099/jgv.0.001728
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