Abstract
Human papillomaviruses (HPV) are strongly associated with cervical intraepithelial neoplasia (CIN) and invasive cancer mainly through the action of the E6 and E7 viral proteins, transcription of which is down-regulated by the E2 protein. To test the hypothesis that HPV 16 E2 variation is important in the development of high-grade squamous neoplasia of the cervix, we carried out a cross-sectional analysis of low-grade and high-grade squamous intraepithelial lesions (SILs) for specific mutations in the HPV 16 E2 gene and for E2 gene disruption in these regions. Isolates were also analysed for the HPV 16 350T-G variant. 22 of 178 low-grade SILs and 43 of 61 high-grade SILs examined, contained HPV 16. No relationship was found between the E6 350T-G variant, or the E2 hinge region 3410C-T variant, and lesion grade. However, disruption of the regions of E2 analysed was significantly more frequent in high-grade lesions, and there was a significant association between the 3684C-A variant in the E2 DNA binding domain and high-grade histology suggesting that this variant may be important in progression to high-grade intraepithelial disease. © 2001 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R Shah KV and the International Biological Study of Cervical Cancer Study Group (1995) Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 87: 796–802
Casas L, Galvan SC, Ordonez RM, Lopez N, Guido M and Berumen J (1999) Asian-American variants of human papillomavirus type 16 have extensive mutations in the E2 gene and are highly amplified in cervical carcinomas. Int J Cancer 83: 449–455
Chang DY, Chen RJ, Lee SC and Huang SC (1997) Prevalence of single and multiple infection with human papillomavirus in various grades of cervical neoplasia. J Med Microbiol 46: 54–60
Dillner J, Zellbi A, Avall-Lundqvist E, Heino P, Eklund C, Pettersson CA, Forslund O, Hannsson BG, Graddien M and Bistoletti P (1995) Association of serum antibodies against defined epitopes of human papillomavirus L1, E2 and E7 antigens and of HPV DNA in incident cervical cancer. Cancer Detect Prev 19: 381–393
Dowhanick JJ, McBride AA and Howley PM (1995) Suppression of cellular proliferation by the papillomavirus E2 protein. J Virol 69: 7791–7799
Emeny RT, Herron JR, Xi LF, Koutsky LA, Kiviat NB and Wheeler CM (1999) Comparison of variant specific hybridisation and single-strand conformational polymorphism methods for detection of mixed human papillomavirus type 16 variant infections. J Clin Microbiol 37: 3627–3633
Gaulthier J-M, Dillner J and Yanin M (1991) Structural analysis of the human papillomavirus type 16 E2 transactivator with antipeptide antibodies reveals a high mobility region linking the transactivation and the DNA binding domains. Nucleic Acids Res 19: 7073–7079
Giannoudis A, Graham DA, Southern SA and Herrington CS (1999) The p53 codon 72 Arg/Pro polymorphism is not related to HPV type or lesion grade in low and high grade squamous intraepithelial lesions and invasive squamous carcinoma of the cervix. Int J Cancer 83: 66–69
Howley PM (1996) Papillomaviridae: the viruses and their replication. Fundamental Virology, (3rd ed) Fields BN, Knipe DM and Howley PM (eds). Lippincott-Raven Publishers: Philadelphia
Jacobs MV, de Roda Husman AM, van den Brule AJC, Snijders PJF, Meijer CJLM and Walboomers JMM (1995) Group-specific differentiation between high and low risk human papillomavirus genotypes by general primer mediated PCR and two cocktails of oligonucleotide probes. J Clin Microbiol 33: 901–905
Kalantari M, Karlsen F, Kristensen G, Holm R, Hagmar B and Johansson B (1998) Disruption of the E1 and E2 reading frames of HPV 16 in cervical carcinoma is associated with poor prognosis. Int J Gynaecol Pathol 17: 146–153
Kovelman R, Bilter GK, Glezer E, Tsou AY and Barbosa MS (1996) Enhanced transcriptional activation by E2 proteins from the oncogenic human papillomaviruses. J Virol 70: 7549–7560
Londesborough P, Ho L, Terry G, Cuzick J, Wheeler C and Singer A (1996) Human papillomavirus genotype as a predictor of persistence and development of histological grade lesions in women with minor cervical abnormalities. Int J Cancer 69: 364–368
Snijders PJF, Van Duin M, Walboomers JMM, Steenbergen RDM, Risse EKJ, Helmerhorst TJM, Verheijen RHM and Meijer CJLM (1998) Telomerase activity exclusively in cervical carcinomas and a subset of cervical intraepithelial neoplasia grade III lesions: strong association with elevated mRNA levels of its catalytic subunit and high-risk human papillomavirus DNA. Cancer Res 58: 3812–3818
Southern SA and Herrington CS (1998) Molecular events in uterine cervical cancer. Sex Transm Inf 74: 101–109
Southern SA, Evans MF and Herrington CS (1997) Basal cell tetrasomy in low grade cervical squamous intraepithelial lesions infected with high risk human papillomaviruses. Cancer Res 57: 4210–4213
Stöppler MC, Ching K, Stöppler H, Clancy K, Schlegel R and Icenogle J (1996) Natural variants of the human papillomavirus type 16 E6 protein differ in their abilities to alter keratinocyte differentiation and to induce p53 degradation. J Virol 70: 6987–6993
Terry G, Ho L and Cuzick J (1997) Analysis of E2 amino acid variants of human papillomavirus types 16 and 18 and their associations with lesion grade and HLA/DR type. Int J Cancer 73: 651–655
Van Duin M, Snijders PJF, Vossen MTM, Klaassen E, Voorhorst F, Verheijen RHM, Helmerhorst TJM, Meijer CJLM and Walboomers JMM (2000) Analysis of human papillomavirus type 16 E6 variants in relation to p53 codon 72 polymorphism genotypes in cervical carcinogenesis. J Gen Virol 81: 317–325
Veress G, Szarka K, Dong X-P, Gergely L and 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
Yamada T, Wheeler CM, Halpern AL, Stewart A-CM, Hildesheim A and Jenison SA (1995) Human papillomavirus type 16 variant lineages in United States populations characterised by nucleotide sequence analysis of the E6, L2 and L1 coding segments. J Virol 69: 7743–7753
Zehbe I and Tomassimo M (1999) The biological significance of human papillomavirus type 16 variants and the development of cervical neoplasia. Papillomavirus Rep 10: 105–116
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Giannoudis, A., van Duin, M., Snijders, P. et al. Variation in the E2-binding domain of HPV 16 is associated with high-grade squamous intraepithelial lesions of the cervix. Br J Cancer 84, 1058–1063 (2001). https://doi.org/10.1054/bjoc.2001.1695
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.1695
Keywords
This article is cited by
-
Molecular variants of human papilloma virus 16 E2, E4, E5, E6 and E7 genes associated with cervical neoplasia in Romanian patients
Archives of Virology (2014)
-
Sequence variation analysis of the E2 gene of human papilloma virus type 16 in cervical lesions from women in Greece
Archives of Virology (2012)
-
Functional implication of sequence variation in the long control region and E2 gene among human papillomavirus type 18 variants
Archives of Virology (2009)
-
Human Papilloma Virus (HPV) and Host Cellular Interactions
Pathology & Oncology Research (2008)
-
The natural history of cervical HPV infection: unresolved issues
Nature Reviews Cancer (2007)