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APOBEC3A associates with human papillomavirus genome integration in oropharyngeal cancers

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Abstract

The prevalence of human papillomavirus (HPV)-related oropharyngeal cancers has been increasing in developed countries. We recently demonstrated that members of the apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3, A3) family, which are antiviral factors, can induce hypermutation of HPV DNA in vitro. In the present study, we found numerous C-to-T and G-to-A hypermutations in the HPV16 genome in oropharyngeal cancer (OPC) biopsy samples using differential DNA denaturation PCR and next-generation sequencing. A3s were more abundantly expressed in HPV16-positive OPCs than in HPV-negative, as assessed using immunohistochemistry and reverse transcription quantitative PCR. In addition, interferons upregulated A3s in an HPV16-positive OPC cell line. Furthermore, quantitative PCR analysis of HPV DNA suggests that APOBEC3A (A3A) expression is strongly correlated with the integration of HPV DNA. These results suggest that HPV16 infection may upregulate A3A expression, thereby increasing the chance of viral DNA integration. The role of A3A in HPV-induced carcinogenesis is discussed.

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References

  1. Bodily J, Laimins LA . Persistence of human papillomavirus infection: keys to malignant progression. Trends Microbiol 2011; 19: 33–39.

    Article  CAS  Google Scholar 

  2. zur Hausen H . Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002; 2: 342–350.

    Article  CAS  Google Scholar 

  3. Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001; 344: 1125–1131.

    Article  CAS  Google Scholar 

  4. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human papillomaviruses. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 90, International Agency for Research on Cancer: Lyon, 2007. 1–636.

  5. Chaturvedi AK, Anderson WF, Lortet-Tieulent J, Curado MP, Ferlay J, Franceschi S et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol 2013; 31: 4550–4559.

    Article  Google Scholar 

  6. Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29: 4294–4301.

    Article  Google Scholar 

  7. Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000; 92: 709–720.

    Article  CAS  Google Scholar 

  8. Pett M, Coleman N . Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007; 212: 356–367.

    Article  CAS  Google Scholar 

  9. Kim SH, Koo BS, Kang S, Park K, Kim H, Lee KR et al. HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation. Int J Cancer 2007; 120: 1418–1425.

    Article  CAS  Google Scholar 

  10. Harris RS, Liddament MT . Retroviral restriction by APOBEC proteins. Nat Rev Immunol 2004; 4: 868–877.

    Article  CAS  Google Scholar 

  11. Golia-Gaur R, Strebel K . HIV-1 Vif, APOBEC, and intrinsic immunity. Retrovirology 2008; 5: 51.

    Article  Google Scholar 

  12. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000; 102: 553–563.

    Article  CAS  Google Scholar 

  13. Burns MB, Temiz NA, Harris RS . Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet 2013; 45: 977–983.

    Article  CAS  Google Scholar 

  14. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet 2013; 45: 970–976.

    Article  CAS  Google Scholar 

  15. Taylor BJ, Nik-Zainal S, Wu YL, Stebbings LA, Raine K, Campbell PJ et al. DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. eLife 2013; 2: e00534.

    Article  Google Scholar 

  16. Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD, Raine K et al. Mutational processes molding the genomes of 21 breast cancers. Cell 2012; 149: 979–993.

    Article  CAS  Google Scholar 

  17. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al. Signatures of mutational processes in human cancer. Nature 2013; 500: 415–421.

    Article  CAS  Google Scholar 

  18. Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 2013; 494: 366–370.

    Article  CAS  Google Scholar 

  19. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499: 214–218.

    Article  CAS  Google Scholar 

  20. Malim MH . APOBEC proteins and intrinsic resistance to HIV-1 infection. Philos Trans R Soc Lond B Biol Sci 2009; 364: 675–687.

    Article  CAS  Google Scholar 

  21. Okeoma CM, Lovsin N, Peterlin BM, Ross SR . APOBEC3 inhibits mouse mammary tumour virus replication in vivo. Nature 2007; 445: 927–930.

    Article  CAS  Google Scholar 

  22. Nguyen DH, Hu J . Reverse transcriptase- and RNA packaging signal-dependent incorporation of APOBEC3G into hepatitis B virus nucleocapsids. J Virol 2008; 82: 6852–6861.

    Article  CAS  Google Scholar 

  23. Bulliard Y, Narvaiza I, Bertero A, Peddi S, Rohrig UF, Ortiz M et al. Structure-function analyses point to a polynucleotide-accommodating groove essential for APOBEC3A restriction activities. J Virol 2011; 85: 1765–1776.

    Article  CAS  Google Scholar 

  24. Gee P, Ando Y, Kitayama H, Yamamoto SP, Kanemura Y, Ebina H et al. APOBEC1-mediated editing and attenuation of herpes simplex virus 1 DNA indicate that neurons have an antiviral role during herpes simplex encephalitis. J Virol 2011; 85: 9726–9736.

    Article  CAS  Google Scholar 

  25. Suspéne R, Aynaud MM, Koch S, Pasdeloup D, Labetoulle M, Gaertner B et al. Genetic editing of herpes simplex virus 1 and Epstein-Barr herpesvirus genomes by human APOBEC3 cytidine deaminases in culture and in vivo. J Virol 2011; 85: 7594–7602.

    Article  Google Scholar 

  26. Vartanian JP, Guetard D, Henry M, Wain-Hobson S . Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science 2008; 320: 230–233.

    Article  CAS  Google Scholar 

  27. Wang Z, Wakae K, Kitamura K, Aoyama S, Liu G, Koura M et al. APOBEC3 deaminases induce hypermutation in human papillomavirus type 16 upon interferon-β stimulation. J Virol 2014; 88: 1308–1317.

    Article  Google Scholar 

  28. Mussil B, Suspene R, Aynaud MM, Gauvrit A, Vartaninan JP, Wain-Hobson S . Human APOBEC3A isoforms translocate to the nucleus and induce DNA double strand breaks leading to cell stress and death. Plos One 2013; 8: e73641.

    Article  CAS  Google Scholar 

  29. Landry S, Narvaiza I, Linfesty DC, Weitzman MD . APOBEC3A can activate the DNA damage response and cause cell-cycle arrest. EMBO Rep 2011; 12: 444–450.

    Article  CAS  Google Scholar 

  30. Suspéne R, Henry M, Guillot S, Wain-Hobson S, Vartanian JP . Recovery of APOBEC3-edited human immunodeficiency virus G->A hypermutants by differential DNA denaturation PCR. J Gen Virol 2005; 86: 125–129.

    Article  Google Scholar 

  31. Suspéne R, Guétard D, Henry M, Sommer P, Wain-Hobson S, Vartanian JP . Extensive editing of both hepatitis B virus DNA strands by APOBEC3 cytidine deaminases in vitro and in vivo. Proc Natl Acad Sci USA 2005; 102: 8321–8326.

    Article  Google Scholar 

  32. Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN et al. DNA deamination mediates innate immunity to retroviral infection. Cell 2003; 113: 803–809.

    Article  CAS  Google Scholar 

  33. Noguchi C, Hiraga N, Mori N, Tsuge M, Imamura M, Takahashi S et al. Dual effect of APOBEC3G on Hepatitis B virus. J Gen Virol 2007; 88: 432–440.

    Article  CAS  Google Scholar 

  34. Robert SA, Gordenin DA . Hypermutation in human cancer genomes: footprints and mechanisms. Nat Rev Cancer 2014; 14: 786–800.

    Article  Google Scholar 

  35. Argyris EG, Acheampong E, Wang F, Huang J, Chen K, Mukhtar M et al. The interferon-induced expression of APOBEC3G in human blood-brain barrier exerts a potent intrinsic immunity to block HIV-1 entry to central nervous system. Virology 2007; 367: 440–451.

    Article  CAS  Google Scholar 

  36. Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS . APOBEC3 proteins mediate the clearance of foreign DNA from human cells. Nat Struct Mol Biol 2010; 17: 222–229.

    Article  CAS  Google Scholar 

  37. Bonvin M, Achermann F, Greeve I, Stroka D, Keogh A, Inderbitzin D et al. Interferon- inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication. Hepatology 2006; 43: 1364–1374.

    Article  CAS  Google Scholar 

  38. Koning FA, Newman EN, Kim EY, Kunstman KJ, Wolinsky SM, Malim MH . Defining APOBEC3 expression patterns in human tissues and hematopoietic cell subsets. J Virol 2009; 83: 9474–9485.

    Article  CAS  Google Scholar 

  39. Steenbergen RD, Hermsen MA, Walboomers JM, Joenje H, Arwert F, Meijer CJ et al. Integrated human papillomavirus type 16 and loss of heterozygosity at 11q22 and 18q21 in an oral carcinoma and its derivative cell line. Cancer Res 1995; 55: 5465–5471.

    CAS  PubMed  Google Scholar 

  40. Roberts I, Ng G, Foster N, Stanley M, Herdman MT, Pett MR et al. Critical evaluation of HPV16 gene copy number quantification by SYBR green PCR. BMC Biotechnol 2008; 8: 57.

    Article  Google Scholar 

  41. Nagao S, Yoshinouchi M, Miyagi Y, Hongo A, Kodama J, Itoh S et al. Rapid and sensitive detection of physical status of human papillomavirus type 16 DNA by quantitative real-time PCR. J Clin Microbiol 2002; 40: 863–867.

    Article  CAS  Google Scholar 

  42. Wilczynski SP, Lin BT, Xie Y, Paz IB . Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma. Am J Pathol 1998; 152: 145–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Warren CJ, Xu T, Guo K, Griffin LM, Westrich JA, Lee D et al. APOBEC3A functions as a restriction factor of human papillomavirus. J Virol 2015; 89: 688–702.

    Article  Google Scholar 

  44. Hoopes JI, Cortez LM, Mertz TM, Malc EP, Mieczkowski PA, Roberts SA . APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication. Cell Rep 2016; 14: 1273–1282.

    Article  CAS  Google Scholar 

  45. Henderson S, Chakravarthy A, Su X, Boshoff C, Fenton TR . APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep 2014; 7: 1833–1841.

    Article  CAS  Google Scholar 

  46. Krokan HE, Sætrom P, Aas PA, Pettersen HS, Kavli B, Slupphaug G . Error-free versus mutagenic processing of genomic uracil–relevance to cancer. DNA Repair (Amst) 2014; 19: 38–47.

    Article  CAS  Google Scholar 

  47. Ohba K, Ichiyama K, Yajima M, Gemma N, Nikaido M, Wu Q et al. In vivo and in vitro studies suggest a possible involvement of HPV infection in the early stage of breast carcinogenesis via APOBEC3B induction. PLoS One 2014; 9: e977787.

    Article  Google Scholar 

  48. Kondo S, Wakisaka N, Muramatsu M, Zen Y, Endo K, Murono S et al. Epstein-Barr virus latent membrane protein 1 induces cancer stem/progenitor-like cells in nasopharyngeal epithelial cell lines. J Virol 2011; 85: 11255–11264.

    Article  CAS  Google Scholar 

  49. Kitamura K, Wang Z, Chowdhury S, Simadu M, Koura M, Muramatsu M . Uracil DNA glycosylase counteracts APOBEC3G-induced hypermutation of hepatitis B viral genomes: excision repair of covalently closed circular DNA. PLoS Pathog 2013; 9: e1003361.

    Article  CAS  Google Scholar 

  50. Liang G, Kitamura K, Wang Z, Liu G, Chowdhury S, Fu W et al. RNA editing of hepatitis B virus transcripts by activation-induced cytidine deaminase. Proc Natl Acad Sci USA 2013; 110: 2246–2251.

    Article  CAS  Google Scholar 

  51. Edge SB, Byrd DR, Carducci MA, Compton CC, Fritz AG, Greene F et al. Cancer Staging Manual 7th ed. American Joint Committee on Cancer (AJCC). Springer: New York, NY, USA, 2009.

    Google Scholar 

  52. Nakanishi Y, Kondo S, Wakisaka N, Tsuji A, Endo K, Murono S et al. Role of activation-induced cytidine deaminase in the development of oral squamous cell carcinoma. PLoS One 2013; 8: e62066.

    Article  CAS  Google Scholar 

  53. Park IS, Chang X, Loyo M, Wu G, Chuang A, Kim MS et al. Characterization of the methylation patterns in human papillomavirus type 16 viral DNA in head and neck cancers. Cancer Prev Res (Phila) 2011; 4: 207–217.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr H Joenje for providing the VU147T cell line. We thank Dr P Howley for providing p1203 PML2d HPV16 and p1321-HPV16 E6/E7. The authors would like to thank Ms A Akita and Ms M Koura for technical assistance. This study was supported by research grants from the Ministry of Education, Science, Sports, Culture and Technology of Japan (A24689064 for SK and B23390396 for TY).

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Correspondence to T Yoshizaki.

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Kondo, S., Wakae, K., Wakisaka, N. et al. APOBEC3A associates with human papillomavirus genome integration in oropharyngeal cancers. Oncogene 36, 1687–1697 (2017). https://doi.org/10.1038/onc.2016.335

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