Integration of human papillomavirus type 16 in cervical cancer cells

• Authors: Zivile Gudleviciene , Daiva Kanopiene , Ausra Stumbryte , Raminta Bausyte , Edgaras Kirvelaitis , Vaida Simanaviciene , Aurelija Zvirbliene
• Languages of publication: EN

Abstracts

EN

Cervical cancer remains an important cause of
women morbidity and mortality. The progression of cervical
pathology correlates with the HPV integration into the host
genome. However, the data on the viral integration status in
cervical dysplasias are controversial. The aim of the current
study was to evaluate the status of HPV integration in two
types of cervical pathology – invasive and non invasive
cervical cancer (e.g. carcinoma in situ). 156 women were
included in the study: 66 women were diagnosed with
invasive cervical cancer (CC) and 90 with non invasive cervical
cancer (carcinoma in situ, CIS). 74.2% [95% PI: 63.64÷84.76]
of specimens collected from women with diagnosed CC
and 85.6% [95% PI: 85.53÷92.85] of CIS specimens were
positive for HPV. The most prevalent HPV genotype in both
groups was HPV16. To evaluate HPV integration, three
selected HPV16 E2 gene fragments were analyzed by PCR.
In the majority of CC and CIS specimens the amplification
of all three HPV16 E2 gene fragments was observed. The
episomal HPV16 form was detected in the majority of CC
and CIS specimens. The deletion of all three HPV16 E2 gene
fragments was detected in 9.4% of CC specimens and 2.2%
of CIS specimens. Finally, integration status could not be
used as diagnostical additional test to distinguish between
invasive and non invasive cervical cancer.

Keywords

EN

cervical cancer; carcinoma in situ; HPV16 integration; HPV16 E2 deletion

• Publisher: De Gruyter Open
• Journal: Open Medicine
• Year: 2014
• Volume: 10
• Issue: 1

Dates

accepted

10 - 6 - 2014

online

25 - 9 - 2014

received

26 - 7 - 2013

Contributors

author

Zivile Gudleviciene

• Institute of Oncology, Vilnius University, Santariskiu str. 1, LT-08660 Vilnius, Lithuania

author

Daiva Kanopiene

• Institute of Oncology, Vilnius University, Santariskiu str. 1, LT-08660 Vilnius, Lithuania

author

Ausra Stumbryte

• Institute of Oncology, Vilnius University, Santariskiu str. 1, LT-08660 Vilnius, Lithuania
• Vilnius University, Universiteto str. 3, LT-01513 Vilnius, Lithuania

author

Raminta Bausyte

• Vilnius University, Universiteto str. 3, LT-01513 Vilnius, Lithuania

author

Edgaras Kirvelaitis

• Vilnius University, Universiteto str. 3, LT-01513 Vilnius, Lithuania

author

Vaida Simanaviciene

• Institute of Biotechnology of Vilnius University, V.A.Graiciuno 8, LT-02241 Vilnius, Lithuania

author

Aurelija Zvirbliene

• Institute of Biotechnology of Vilnius University, V.A.Graiciuno 8, LT-02241 Vilnius, Lithuania

References

• [1] Arbyn M, Anttila A, Jordan J, Ronco G, Schenck U, SegnanN, Wiener H, Herbert A, von Karsa L: European Guidelinesfor Quality Assurance in Cervical Cancer Screening. SecondEdition-Summary Document. Ann Oncol 2010;21(3):448–458.[Crossref]
• [2] Anttila A, Ronco G: Description of the national situation ofcervical cancer screening in the member states of the EuropeanUnion. Eur J Cancer 2009;45(15):2685-708.[WoS][Crossref]
• [3] Cheung JL, Lo KW, Cheung TH, Tang JW, Chan PK: Viral load,E2 gene disruption status, and lineage of human papillomavirustype 16 infection in cervical neoplasia. J Infect Dis2006;194(12):1706-12.
• [4] Barzon L, Giorgi C, Buonaguro FM, Palù G: Italian Society forVirology. Guidelines of the Italian Society for Virology on HPVtesting and vaccination for cervical cancer prevention. InfectAgent Cancer 2008;3:14.[Crossref]
• [5] Bosch FX, Lorincz A, Muñoz N, Meijer CJ, Shah KV: The causalrelation between human papillomavirus and cervical cancer. JClin Pathol 2002;55(4):244-65.[Crossref]
• [6] Woodman CBJ, Collins SI, Young LS: The natural history ofcervical HPV infection. Nat Rev Cancer 2007;7(1):11-22.[WoS][Crossref]
• [7] Pett M, Coleman N: Integration of high-risk human papillomavirus:a key event in cervical carcinogenesis? J Pathol2007;212(4):356-67.[Crossref][WoS]
• [8] Cheung JL, Lo KW, Cheung TH, Tang JW, Chan PK: Viral load,E2 gene disruption status, and lineage of human papillomavirustype 16 infection in cervical neoplasia. J Infect Dis2006;194(12):1706-12.
• [9] Cheung JK, Cheung, TH, Ng CW, Yu MY, Wong MC, Siu SS et al.:Analysis of human papillomavirus type 18 load and integrationstatus from low-grade cervical lesion to invasive CervicalCancer. J Clin Microbiol 2009;47(2):287-93.[WoS][Crossref]
• [10] Kulmala SM, Syrjänen SM, Gyllensten UB, Shabalova IP,Petrovichev N, Tosi P et al.: Early integration of high copyHPV16 detectable in women with normal and low grade cervicalcytology and histology. J Clin Pathol 2006;59(5):513-7.[Crossref]
• [11] Huang LW, Chao SL, Lee BH: Integration of human papillomavirustype-16 and type-18 is a very early event in cervicalcarcinogenesis. J Clin Pathol 2008;61(5):627-31.[Crossref][WoS]
• [12] Collins SI, Constandinou-Williams C, Wen K, Young LS, RobertsS, Murray PG et al.: Disruption of the E2 Gene is a common andearly event in the natural history of cervical human papillomavirusinfection: a longitudinal cohort study. Cancer Res2009;69(9):3828-32.[WoS]
• [13] Wentzensen N, Vinokurova S, von Doeberitz MK: Systematicreview of genomic integration sites of human papillomavirusgenomes in epithelial dysplasia and invasive cancer of thefemale lower genital tract. Cancer Res 2004;64:3878–3884.[Crossref]
• [14] Arias-Pulido H, Peyton CL, Joste NE, Vargas H, WheelerCM: Human Papillomavirus Type 16 Integration in CervicalCarcinoma In Situ and in Invasive Cervical Cancer. J ClinMicrobiol 2006;44(5):1755–1762.
• [15] De Roda Husman AM, Walboomers JM, van den Brule AJ,Meijer CJ, Snijders PJ: The use of general primers GP5 andGP6 elongated at their 3’ ends with adjacent highly conservedsequences improves human papillomavirus detection by PCR. JGen Virol 1995;76:1057-1062.
• [16] Gravitt PE, Peyton CL, Alessi TQ, Wheeler CM, Coutlee F,Hildesheim A, Schiffman MH, Scott DR, Apple RJ: Improvedamplification of genital human papillomaviruses. J ClinMicrobiol 2000;38(1):357–361.
• [17] Popendikyte V, Gulbinovic I, Paulauskiene V, Paulauskas D:High risk human papilloma virus detection and genotyping bymultiplex PCR. Lietuvos akuserija ir ginekologija (in Lithuanian)2008;11(4):348-352.
• [18] Graham DA, Herrington CS: HPV-16 E2 gene disruption andsequence variation in CIN 3 lesions and invasive squamous cellcarcinomas of the cervix: relation to numerical chromosomeabnormalities. Mol Pathol 2000;53:201–6.
• [19] Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X,Shah KV, Snijders PJ, Meijer CJ: Epidemiologic classification ofhuman papillomavirus types associated with cervical cancer. NEngl J Med 2003;348:518–527.
• [20] Munoz N, Castellsague X, de Gonzalez AB, Gissmann L:Chapter 1: HPV in the etiology of human cancer. Vaccine2006;24 (Suppl 3):1–10.[Crossref]
• [21] IARC Monographs on the Evaluation of Carcinogenic Risks toHumans. Vol. 90, Human Papillomaviruses, IARC Monographs2007.
• [22] Gudlevicienė Z, Didziapetriene J, Ramael M, Uleckiene S,Valuckas KP: Human papillomavirus and p53 polymorphismin Lithuanian cervical cancer patients. Gynecol Oncol2006;102(3):530-3.
• [23] Sepetiene A, Gudleviciene Z, Bumbuliene Z, DrasutieneG, Didziapetriene J: State of HPV16 integration inLithuanian women with cervical neoplasia. Centr Eur J Med2011;6(2):205-212.
• [24] Clifford GM, Gallus S, Herrero R, Muñoz N, Snijders PJ,Vaccarella S, et al.: Worldwide distribution of humanpapillomavirus types in cytologically normal women in theInternational Agency for Research on Cancer HPV prevalencesurveys: a pooled analysis. Lancet 2005;366(9490):991-8.
• [25] Bosch FX, de Sanjosé S: The epidemiology of humanpapillomavirus infection and cervical cancer. Dis Markers2007;23(4):213-37.[WoS][Crossref]
• [26] Castellsague X, de Sanjose S, Aguado T, Louie KS, Bruni L,Munoz J, et al.: HPV and cervical cancer in the World. 2007Report. Vaccine 2007;25S:C1-26.
• [27] Stanley M: Pathology and epidemiology of HPV infection infemales. Gynecol Oncol 2010;117(2):S5-S10.[WoS]
• [28] Peitsaro P, Johansson B, Syrjanen S: Integrated humanpapillomavirus type 16 is frequently found in cervical cancerprecursors as demonstrated by a novel quantitative real-timePCR technique. J Clin Microbiol 2002;40:886–891.[Crossref]
• [29] Hudelist G, Manavi M, Pischinger KI, Watkins-Riedel T, SingerCF, Kubista E, Czerwenka KF: Physical state and expression ofHPV DNA in benign and dysplastic cervical tissue: differentlevels of viral integration are correlated with lesion grade.Gynecol Oncol 2004;92:873–880.[Crossref]
• [30] Cricca M, Morselli-Labate AM, Venturoli S, Ambretti S,Gentilomi GA, Gallinella G, Costa S, Musiani M, Zerbini M: ViralDNA load, physical status and E2/E6 ratio as markers to gradeHPV16 positive women for high-grade cervical lesions. GynecolOncol 2007;106:549–557.
• [31] Vinokurova S, Wentzensen N, Kraus I, Klaes R, Driesch C,Melsheimer P, Kisseljov F, Durst M, Schneider A, von KnebelDoeberitz M: Typedependent integration frequency of humanpapillomavirus genomes in cervical lesions. Cancer Res2008;68:307–313.[Crossref]
• [32] Nagao S, Yoshinouchi M, Miyagi Y, Hongo A, Kodama J, ItohS, Kudo T: Rapid and sensitive detection of physical status ofhuman papillomavirus type 16 DNA by quantitative real-timePCR. J Clin Microbiol 2002;40:863–867.[Crossref]
• [33] Ramanakumar AV, Goncalves O, Richardson H, Tellier P,Ferenczy A, Coutlée F, Franco EL: Human papillomavirus(HPV) types 16, 18, 31, 45 DNA loads and HPV-16 integrationin persistent and transient infections in young women. BMCInfect Dis 2010;10:326 in http://www.biomedcentral.com/1471-2334/10/326.
• [34] Theelen W, Speel EJM, Herfs M, Reijans M, Simons G,Meulemans EV, Baldewijns MM, Ramaekers FCS, SomjaJ, Delvenne P, Hopman AHN: Increase in Viral Load, ViralIntegration, and Gain of Telomerase Genes during UterineCervical Carcinogenesis can be Simultaneously Assessed bythe HPV 16/18 MLPA-Assay. Am J Pathol 2010;177(4):2022-33.[WoS]
• [35] Theelen W, Reijans M, Simons G, Ramaekers FCS, Speel EJM,Hopman AHN: A new multiparameter assay to assess HPV 16/18viral load and physical status together with gain of telomerasegenes in HPV-related cancers. Int J Cancer 2010;126:959–975.[WoS]

Identifiers

DOI

10.1515/med-2015-0001