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Human papillomavirus (HPV) E6/E7 mRNA detection in cervical exfoliated cells: a potential triage for HPV-positive women

宫颈脱落细胞人乳头瘤病毒(HPV)E6/E7 mRNA检测在HPV 阳性女性筛查中的应用

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Abstract

Cytology triage has been generally recommended for human papillomavirus (HPV)-positive women, but is highly dependent on well-trained cytologists. The present study was designed to explore whether HPV E6/E7 mRNA detection in cervical exfoliated cells can be a potential triage for HPV-positive women from a clinic-based population. Both the primary HPV testing and Papanicolaou (Pap) test were performed on all eligible HPV-positive women. HPV E6/E7 mRNA was detected by QuantiVirus® HPV E6/E7 mRNA assay in cervical exfoliated cells. All HPV-positive women underwent colposcopy and further biopsy if indicated. The data were assessed by Pearson’s Chi-squared test and the receiver operating characteristic curve. A total of 404 eligible HPV-positive women were enrolled. Positive rate of E6/E7 mRNA in high-grade squamous intraepithelial lesion (HSIL) cases was higher than that in low-grade squamous intraepithelial lesion (LSIL) or normal cases. There was no statistical difference found between mRNA and cytological testing with sensitivity (89.52% vs. 86.67%, P=0.671), specificity (48.96% vs. 48.96%, P=1.000), positive predictive value (39.00% vs. 38.24%, P=1.000), and negative predictive value (92.76% vs. 90.97%, P=0.678) for detecting ≥HSIL. HPV E6/E7 mRNA detection in cervical exfoliated cells shows the same performance as Pap triage for HSIL identification for HPV-positive women. Detection of HPV E6/E7 mRNA may be used as a new triage option for HPV-positive women.

概要

目的

基于临床样本探讨宫颈脱落细胞HPV E6/E7mRNA检测能否作为HPV阳性女性的筛查手段。

创新点

首次比较了宫颈脱落细胞HPV E6/E7 mRNA 检测与宫颈脱落细胞学检测对于HPV 阳性女性宫颈活检结果的预测价值。

方法

所有入组的HPV 阳性女性均进行宫颈脱落细胞学及HPV E6/E7 mRNA 检测。比较两种方法对于宫颈活检结果的预测价值。

结论

对于HPV 阳性的女性,高级别鳞状上皮内病变(HSIL)HPV E6/E7 mRNA 阳性率高于低级别鳞状上皮内病变(LSIL)及正常病例。HPV E6/E7mRNA 与细胞学检测相比,HSIL 及以上级别病变的检测敏感性(89.52% vs. 86.67%,P=0.671)、特异性(48.96% vs. 48.96%,P=1.000)、阳性预测值(39.00% vs. 38.24%,P=1.000)及阴性预测值(92.76% vs. 90.97%,P=0.678)均无显著差异。HPV E6/E7 mRNA 检测或能成为HPV阳性女性的一种新的筛查手段。

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References

  • Arbyn, M., Ronco, G., Anttila, A., et al., 2012. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine, 30(5):F88–F99. http://dx.doi.org/10.1016/j.vaccine.2012.06.095

    Article  PubMed  Google Scholar 

  • Benevolo, M., Vocaturo, A., Caraceni, D., et al., 2011. Sensitivity, specificity, and clinical value of human papillomavirus (HPV) E6/E7 mRNA assay as a triage test for cervical cytology and HPV DNA test. J. Clin. Microbiol., 49(7):2643–2650. http://dx.doi.org/10.1128/JCM.02570-10

    Article  PubMed  PubMed Central  Google Scholar 

  • Castle, P.E., Dockter, J., Giachetti, C., et al., 2007. A crosssectional study of a prototype carcinogenic human papillomavirus E6/E7 messenger RNA assay for detection of cervical precancer and cancer. Clin. Cancer Res., 13(9):2599–2605. http://dx.doi.org/10.1158/1078-0432.CCR-06-2881

    Article  CAS  PubMed  Google Scholar 

  • Chellappan, S., Kraus, V.B., Kroger, B., et al., 1992. Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. PNAS, 89(10):4549–4553. http://dx.doi.org/10.1073/pnas.89.10.4549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clifford, G.M., Smith, J.S., Aguado, T., et al., 2003. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Br. J. Cancer, 89(1):101–105. http://dx.doi.org/10.1038/sj.bjc.6601024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Condel, J.L., Mahood, L.K., Grzybicki, D.M., et al., 2002. Papanicolaou tests diagnosed as atypical by a cytotechnologist and downgraded to benign by a pathologist: a measure of laboratory quality. Am. J. Clin. Pathol., 117(4):534–540. http://dx.doi.org/10.1309/WVW0-48TJ-E7VA-DM8R

    Article  PubMed  Google Scholar 

  • Coquillard, G., Palao, B., Patterson, B.K., 2011. Quantification of intracellular HPV E6/E7 mRNA expression increases the specificity and positive predictive value of cervical cancer screening compared to HPV DNA. Gynecol. Oncol., 120(1):89–93. http://dx.doi.org/10.1016/j.ygyno.2010.09.013

    Article  CAS  PubMed  Google Scholar 

  • Cuschieri, K., Wentzensen, N., 2008. Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol. Biomarkers Prev., 17(10):2536–2545. http://dx.doi.org/10.1158/1055-9965.EPI-08-0306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Sanjose, S., Diaz, M., Castellsague, X., et al., 2007. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect. Dis., 7(7):453–459. http://dx.doi.org/10.1016/S1473-3099(07)70158-5

    Article  PubMed  Google Scholar 

  • Discacciati, M.G., Da, S.I., Villa, L.L., et al., 2014. Prognostic value of DNA and mRNA E6/E7 of human papillomavirus in the evolution of cervical intraepithelial neoplasia grade 2. Biomark Insights, 9:15–22. http://dx.doi.org/10.4137/BMI.S14296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franceschi, S., Denny, L., Irwin, K.L., et al., 2011. Eurogin 2010 roadmap on cervical cancer prevention. Int. J. Cancer, 128(12):2765–2774. http://dx.doi.org/10.1002/ijc.25915

    Article  CAS  PubMed  Google Scholar 

  • Giorgi Rossi, P., Benevolo, M., Vocaturo, A., et al., 2013. Prognostic value of HPV E6/E7 mRNA assay in women with negative colposcopy or CIN1 histology result: a follow-up study. PLoS ONE, 8(2):e57600. http://dx.doi.org/10.1371/journal.pone.0057600

    Article  PubMed  PubMed Central  Google Scholar 

  • Ho, C.M., Lee, B.H., Chang, S.F., et al., 2010. Type-specific human papillomavirus oncogene messenger RNA levels correlate with the severity of cervical neoplasia. Int. J. Cancer, 127(3):622–632. http://dx.doi.org/10.1002/ijc.25078

    Article  CAS  PubMed  Google Scholar 

  • Jeantet, D., Schwarzmann, F., Tromp, J., et al., 2009. NucliSENS EasyQ HPV v1 test—testing for oncogenic activity of human papillomaviruses. J. Clin. Virol., 45(1):S29–S37. http://dx.doi.org/10.1016/S1386-6532(09)70006-X

    Article  CAS  PubMed  Google Scholar 

  • Kitchener, H.C., Almonte, M., Thomson, C., et al., 2009. HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC):a randomised controlled trial. Lancet Oncol., 10(7):672–682. http://dx.doi.org/10.1016/S1470-2045(09)70156-1

    Article  PubMed  Google Scholar 

  • Liu, T.Y., Xie, R., Luo, L., et al., 2014. Diagnostic validity of human papillomavirus E6/E7 mRNA test in cervical cytological samples. J. Virol. Methods, 196:120–125. http://dx.doi.org/10.1016/j.jviromet.2013.10.032

    Article  CAS  PubMed  Google Scholar 

  • Mayrand, M.H., Duarte-Franco, E., Rodrigues, I., et al., 2007. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N. Engl. J. Med., 357(16):1579–1588. http://dx.doi.org/10.1056/NEJMoa071430

    Article  CAS  PubMed  Google Scholar 

  • Moyer, V.A., 2012. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med., 156(12):880–891. http://dx.doi.org/10.7326/0003-4819-156-12-201206190-00424

    Article  PubMed  Google Scholar 

  • Naucler, P., Ryd, W., Tornberg, S., et al., 2007. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N. Engl. J. Med., 357(16):1589–1597. http://dx.doi.org/10.1056/NEJMoa073204

    Article  CAS  PubMed  Google Scholar 

  • Pierry, D., Weiss, G., Lack, B., et al., 2012. Intracellular human papillomavirus E6, E7 mRNA quantification predicts CIN 2+ in cervical biopsies better than Papanicolaou screening for women regardless of age. Arch. Pathol. Lab. Med., 136(8):956–960. http://dx.doi.org/10.5858/arpa.2011-0180-OA

    Article  PubMed  Google Scholar 

  • Ronco, G., Giorgi-Rossi, P., Carozzi, F., et al., 2010. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol., 11(3):249–257. http://dx.doi.org/10.1016/S1470-2045(09)70360-2

    Article  CAS  PubMed  Google Scholar 

  • Scheffner, M., Werness, B.A., Huibregtse, J.M., et al., 1990. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell, 63(6):1129–1136. http://dx.doi.org/10.1016/0092-8674(90)90409-8

    Article  CAS  PubMed  Google Scholar 

  • Scheurer, M.E., Tortolero-Luna, G., Adler-Storthz, K., 2005. Human papillomavirus infection: biology, epidemiology, and prevention. Int. J. Gynecol. Cancer, 15(5):727–746. http://dx.doi.org/10.1111/j.1525-1438.2005.00246.x

    Article  CAS  PubMed  Google Scholar 

  • Schiffman, M., Wentzensen, N., Wacholder, S., et al., 2011. Human papillomavirus testing in the prevention of cervical cancer. J. Natl. Cancer Inst., 103(5):368–383. http://dx.doi.org/10.1093/jnci/djq562

    Article  PubMed  PubMed Central  Google Scholar 

  • Siebers, A.G., Klinkhamer, P.J., Grefte, J.M., et al., 2009. Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. JAMA, 302(16):1757–1764. http://dx.doi.org/10.1001/jama.2009.1569

    Article  CAS  PubMed  Google Scholar 

  • Sorbye, S.W., Arbyn, M., Fismen, S., et al., 2011. HPV E6/E7 mRNA testing is more specific than cytology in postcolposcopy follow-up of women with negative cervical biopsy. PLoS ONE, 6(10):e26022. http://dx.doi.org/10.1371/journal.pone.0026022

    Article  PubMed  PubMed Central  Google Scholar 

  • Sotlar, K., Stubner, A., Diemer, D., et al., 2004. Detection of high-risk human papillomavirus E6 and E7 oncogene transcripts in cervical scrapes by nested RT-polymerase chain reaction. J. Med. Virol., 74(1):107–116. http://dx.doi.org/10.1002/jmv.20153

    Article  CAS  PubMed  Google Scholar 

  • Tavassoéli, F.A., Devilee, P., 2003. Pathology and Genetics Tumours of the Breast and Female Genital Organs. IARC Press, Lyon, France.

    Google Scholar 

  • Torre, L.A., Bray, F., Siegel, R.L., et al., 2015. Global cancer statistics, 2012. CA Cancer J. Clin., 65(2):87–108. http://dx.doi.org/10.3322/caac.21262

    Article  PubMed  Google Scholar 

  • Walboomers, J.M., Jacobs, M.V., Manos, M.M., et al., 1999. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol., 189(1):12–19. http://dx.doi.org/10.1002/(SICI)1096-9896(199909)189:1 <12::AID-PATH431>3.0.CO;2-F

    Article  CAS  PubMed  Google Scholar 

  • Wright, T.J., Schiffman, M., 2003. Adding a test for human papillomavirus DNA to cervical-cancer screening. N. Engl. J. Med., 348(6):489–490. http://dx.doi.org/10.1056/NEJMp020178

    Article  PubMed  Google Scholar 

  • Zappacosta, R., Caraceni, D., Ciccocioppo, L., et al., 2013. Implementing specificity of HPV-DNA primary screening in a successful organised cervical cancer prevention programme. Gynecol. Oncol., 128(3):427–432. http://dx.doi.org/10.1016/j.ygyno.2012.11.030

    Article  PubMed  Google Scholar 

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Correspondence to Ye-li Yao or Wei-guo Lu.

Additional information

Project supported by the Special Fund for Scientific Research in the Public Interest from the National Health and Family Planning Commission of the People’s Republic of China (No. 201402010), the National Key Technology R & D Program of China (No. 2016YFC1302900), the Zhejiang Provincial Educational Project (No. Y201328819), the Zhejiang Provincial Medical & Hygienic Science and Technology Project (Nos. 2013KYB147 and 2013KYA104), and the Zhejiang Provincial Natural Science Foundation (No. LQ14H160007), China

ORCID: Ye-li YAO, http://orcid.org/0000-0003-4014-4052

Compliance with ethics guidelines

Ye-li YAO, Qi-fang TIAN, Bei CHENG, Yi-fan CHENG, Jing YE, and Wei-guo LU declare that they have no conflict of interest.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study.

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Yao, Yl., Tian, Qf., Cheng, B. et al. Human papillomavirus (HPV) E6/E7 mRNA detection in cervical exfoliated cells: a potential triage for HPV-positive women. J. Zhejiang Univ. Sci. B 18, 256–262 (2017). https://doi.org/10.1631/jzus.B1600288

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  • DOI: https://doi.org/10.1631/jzus.B1600288

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