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  • Genetics and Genomics
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Variants of the long control region and the E6 oncogene in European human papillomavirus type 16 isolates: implications for cervical disease

Abstract

High-risk human papillomavirus types, especially type 16, are risk factors for cervical cancer. Preliminary studies suggest that HPV16 polymorphisms in the long control region or in the E6 gene may alter the oncogenic potential of the virus. This could partially explain why some lesions progress to cancer while others do not. A systematic study combining the long control region and E6 has not been undertaken. This prompted us to investigate the long control region and the E6 in northern European women infected with human papillomavirus 16. We identified the sequence variations of both regions and investigated the long control region promoter activity among various isolates. In addition, we correlated the distribution of long control region and E6 polymorphisms with disease status. We analyzed 45 samples from Swedish and Finnish women. The long control region and the E6 gene were sequenced after polymerase chain reaction long control region fragments of six European isolates covering the majority of polymorphisms in this region were ligated into the pALuc vector and used for luciferase assays. In European HPV16 isolates, polymorphisms in the long control region are more frequent than in the E6 gene. Nevertheless, the promoter function was slightly increased in only one of the tested European long control region variants. In addition, we found a specific European E6 variant, L83V, to be enriched in high-grade lesions and cancer rather than a specific European long control region variant. The difference in oncogenicity between European HPV16 genotypes is more probably due to an altered property of the corresponding E6 proteins rather than to an altered activity of the P97 promoter.

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References

  • Chong T, Apt D, Gloss B, Isa M, Bernard HU (1991) The enhancer of human papillomavirus type 16: binding sites for the ubiquitous transcription factors oct-1, NFA, TEF-2, NF1, and AP-1 participate in epithelial cell-specific transcription. J Virol 65: 5933–5943

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dong XP, Stubenrauch F, Beyer-Finkler E, Pfister H (1994) Prevalence of deletions of YY1-binding sites in episomal HPV 16 DNA from cervical cancers. Int J Cancer 58: 803–808

    Article  CAS  Google Scholar 

  • Hildesheim A, Schiffman M, Bromley C, Wacholder S, Herrero R, Rodriguez A, Bratti MC, Sherman ME, Scarpidis U, Lin QQ, Terai M, Bromley RL, Buetow K, Apple RJ, Burk RD (2001) Human papillomavirus type 16 variants and risk of cervical cancer. J Natl Cancer Inst 93: 315–318

    Article  CAS  Google Scholar 

  • Kämmer C, Warthorst U, Torrez-Martinez N, Wheeler CM, Pfister H (2000) Sequence analysis of the long control region of human papillomavirus type 16 variants and functional consequences for P97 promoter activity. J Gen Virol 81: 1975–1981

    Article  Google Scholar 

  • Kurvinen K, Yliskoski M, Saarikoski S, Syrjanen K, Syrjanen S (2000) Variants of the long control region of human papillomavirus type 16. Eur J Cancer 36: 1402–1410

    Article  CAS  Google Scholar 

  • Nindl I, Rindfleisch K, Lotz B, Schneider A, Dürst M (1999) Uniform distribution of HPV16 E6 and E7 variants in patients with normal histology, cervical intraepithelial neoplasia and cervical cancer. Int J Cancer 82: 203–207

    Article  CAS  Google Scholar 

  • O'Connor MJ, Tan SH, Tan CH, Bernard HU (1996) YY1 represses human papillomavirus type 16 transcription by quenching AP-1 activity. J Virol 70: 6529–6539

    CAS  PubMed  PubMed Central  Google Scholar 

  • Phelps WC, Münger K, Yee CL, Barnes JA, Howley PM (1992) Structure-function analysis of the human papillomavirus type 16 E7 oncoprotein. J Virol 66: 2418–2427

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63: 1129–1136

    Article  CAS  Google Scholar 

  • Seedorf K, Krammer G, Durst M, Suhai S, Rowekamp WG (1985) Human papillomavirus type 16 DNA sequence. Virology 145: 181–185

    Article  CAS  Google Scholar 

  • Veress G, Szarka K, Dong XP, Gergely L, Pfister H (1999) Functional significance of sequence variation in the E2 gene and the long control region of human papillomavirus type 16. J Gen Virol 80: 1035–1043

    Article  CAS  Google Scholar 

  • Villa LL, Sichero L, Rahal P, Caballero O, Ferenczy A, Rohan T, Franco EL (2000) Molecular variants of human papillomavirus types 16 and 18 preferentially associated with cervical neoplasia. J Gen Virol 81: 2959–2968

    Article  CAS  Google Scholar 

  • Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189: 12–19

    Article  CAS  Google Scholar 

  • Xi LF, Koutsky LA, Galloway DA, Kuypers J, Hughes JP, Wheeler CM, Holmes KK, Kiviat NB (1997) Genomic variation of human papillomavirus type 16 and risk for high grade cervical intraepithelial neoplasia. [see comments] J Natl Cancer Inst 89: 796–802

    Article  CAS  Google Scholar 

  • Yamada T, Manos MM, Peto J, Greer CE, Munoz N, Bosch FX, Wheeler CM (1997) Human papillomavirus type 16 sequence variation in cervical cancers: a worldwide perspective. J Virol 71: 2463–2472

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zehbe I, Voglino G, Delius H, Wilander E, Tommasino M (1998a) Risk of cervical cancer and geographical variations of human papillomavirus 16 E6 polymorphisms. [letter] Lancet 352: 1441–1442

    Article  CAS  Google Scholar 

  • Zehbe I, Wilander E, Delius H, Tommasino M (1998b) Human papillomavirus 16 E6 variants are more prevalent in invasive cervical carcinoma than the prototype. Cancer Res 58: 829–833

    CAS  PubMed  Google Scholar 

  • Zehbe I, Voglino G, Wilander E, Delius H, Marongiu A, Edler L, Klimek F, Andersson S, Tommasino M (2001a) p53 codon 72 polymorphism and various human papillomavirus 16 E6 genotypes are risk factors for cervical cancer development. Cancer Res 61: 608–611

    CAS  PubMed  Google Scholar 

  • Zehbe I, Tachezy R, Mytilineos J, Voglino G, Mikyskova I, Delius H, Marongiu A, Gissmann L, Wilander E, Tommasino M (2001b) Human papillomavirus 16 E6 polymorphisms in cervical lesions from different European populations and their correlation with human leukocyte antigen class II haplotypes. Int J Cancer 94: 711–716

    Article  CAS  Google Scholar 

  • zur Hausen H (1991) Human papillomaviruses in the pathogenesis of anogenital cancer. Virology 184: 9–13

    Article  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank Professors Lutz Gissmann and Harald zur Hausen for kind support. This work was partially supported by the Deutsche Forschungsgesellschaft, Sonderforschungsbereich (274), Cologne, Germany and the Wilhelm Sander-Stiftung (98.065.1), Munich, Germany.

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Correspondence to I Zehbe.

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Kämmer, C., Tommasino, M., Syrjänen, S. et al. Variants of the long control region and the E6 oncogene in European human papillomavirus type 16 isolates: implications for cervical disease. Br J Cancer 86, 269–273 (2002). https://doi.org/10.1038/sj.bjc.6600024

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