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Review

Cervical cancer risk profiling: molecular biomarkers predicting the outcome of hrHPV infection

ORCID Icon, , , &
Pages 1099-1120 | Received 09 Jun 2020, Accepted 08 Oct 2020, Published online: 25 Oct 2020

References

  • Ferlay J, e.a. global cancer observatory: cancer today. Lyon, France: international agency for research on cancer. 2018 [cited 2020 January 1]; Available from: https://gco.iarc.fr/today
  • Doorbar J, Quint W, Banks L, et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30(Suppl 5):F55–70. DOI:10.1016/j.vaccine.2012.06.083.
  • Heideman DAM, Hesselink AT, Berkhof J, et al. Clinical validation of the cobas 4800 HPV test for cervical screening purposes. J Clin Microbiol. 2011;49(11):3983–3985. DOI:10.1128/JCM.05552-11.
  • Ghosh T, VandeHaar MA, Rivera M, et al. High-risk HPV genotype distribution in HPV co-test specimens: study of a predominantly Midwestern population. J Am Soc Cytopathol. 2018;7(2):99–105. DOI:10.1016/j.jasc.2017.09.007
  • Molijn A, Jenkins D, Chen W, et al. The complex relationship between human papillomavirus and cervical adenocarcinoma. Int J Cancer. 2016;138(2):409–416. DOI:10.1002/ijc.29722.
  • Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005;32:7–15. (1386–6532 (Print)). DOI:10.1016/j.jcv.2004.12.006.
  • Griffin H, Soneji Y, Van Baars R, et al. Stratification of HPV-induced cervical pathology using the virally encoded molecular marker E4 in combination with p16 or MCM. Mod Pathol. 2015;28(7): 977–993. DOI:10.1038/modpathol.2015.52. .
  • Schiller JT, Day PM, Kines RC. Current understanding of the mechanism of HPV infection. Gynecol Oncol. 2010;118(1 Suppl):S12–S17.
  • Horvath CAJ, Boulet GA, Renoux VM, et al. Mechanisms of cell entry by human papillomaviruses: an overview. Virol J. 2010;7(1):11–11. DOI:10.1186/1743-422X-7-11.
  • Tsakogiannis D, Gartzonika C, Levidiotou-Stefanou S, et al. Molecular approaches for HPV genotyping and HPV-DNA physical status. Expert Rev Mol Med. 2017;19:e1.
  • Stevenson A, Kavanagh K, Pan J, et al. Risk stratification of cervical disease using detection of human papillomavirus (HPV) E4 protein and cellular MCM protein in clinical liquid based cytology samples. J Clin Virol. 2018;108:19–25.
  • Middleton K, Peh W, Southern S, et al. Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers. J Virol. 2003;77(19):10186–10201. DOI:10.1128/JVI.77.19.10186-10201.2003.
  • Mello V, S.R. cancer, cervical intraepithelial neoplasia (CIN). Treasure Island (FL): StatPearls Publishing; 2020 Jan- 2019 [cited 2020 January 2]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK544371/
  • Ebisch RMF, Ketelaars PJW, van der Sanden WMH, et al. Screening for persistent high-risk HPV infections may be a valuable screening method for young women; a retrospective cohort study. Plos One. 2018;13(10):e0206219. DOI:10.1371/journal.pone.0206219.
  • Liu Y, Zhang C, Gao W, et al. Genome-wide profiling of the human papillomavirus DNA integration in cervical intraepithelial neoplasia and normal cervical epithelium by HPV capture technology. Sci Rep. 2016;6(1):35427. DOI:10.1038/srep35427.
  • Melsheimer P, Vinokurova S, Wentzensen N, et al. DNA aneuploidy and integration of human papillomavirus type 16 E6/E7 oncogenes in intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix uteri. Clin Cancer Res. 2004;10(9):3059. DOI:10.1158/1078-0432.CCR-03-0565.
  • Van Tine BA, Kappes JC, Banerjee NS, et al. Clonal selection for transcriptionally active viral oncogenes during progression to cancer. J Virol. 2004;78(20):11172–11186. DOI:10.1128/JVI.78.20.11172-11186.2004.
  • Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol. 2007;212(4):356–367.
  • Wilting SM, Steenbergen RDM, Tijssen M, et al. Chromosomal signatures of a subset of high-grade premalignant cervical lesions closely resemble invasive carcinomas. Cancer Res. 2009;69(2):647. DOI:10.1158/0008-5472.CAN-08-2478.
  • Huh W, Einstein MH, Herzog TJ, et al. What is the role of HPV typing in the United States now and in the next five years in a vaccinated population? Gynecol Oncol. 2010;117(3):481–485. DOI:10.1016/j.ygyno.2010.01.037.
  • Dillner J, Rebolj M, Birembaut P, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337(oct13 1):a1754–a1754. DOI:10.1136/bmj.a1754.
  • Cibas ES. Chapter 1 - cervical and vaginal cytology. In: Cibas ES, Ducatman BS, editors. Cytology. Third ed. Philadelphia: W.B. Saunders; 2009. p. 1–63.
  • Palmer T, Wallace L, Pollock KG, et al. Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study. BMJ. 2019;365:l1161.
  • Felix JC, Wright TC, Amezcua CA. CHAPTER 36 - Cervix. Weidner N, Cote RJ, et al., editors. Modern Surgical Pathology (Second Edition), W.B. Saunders, 2009, p. 1263–1294, ISBN 9781416039662. http://www.sciencedirect.com/science/article/pii/B9781416039662000369 DOI 10.1016/B978–1–4160–3966–2.00036–9
  • Ketelaars PJW, Bosgraaf RP, Siebers AG, et al. High-risk human papillomavirus detection in self-sampling compared to physician-taken smear in a responder population of the Dutch cervical screening: results of the VERA study. Prev Med. 2017;101:96–101.
  • Polman NJ, Ebisch RM, Heideman DA, et al. Performance of human papillomavirus testing on self-collected versus clinician-collected samples for the detection of cervical intraepithelial neoplasia of grade 2 or worse: a randomised, paired screen-positive, non-inferiority trial. Lancet Oncol. 2019;20(2):229–238.
  • Schmeink CE, Bekkers RL, Massuger LF, et al. The potential role of self-sampling for high-risk human papillomavirus detection in cervical cancer screening. Rev Med Virol. 2011;21(3):139–153.
  • Winer RL, Lin J, Tiro JA, et al. Effect of mailed human papillomavirus test kits vs usual care reminders on cervical cancer screening uptake, precancer detection, and treatment: a randomized clinical trial. JAMA Network Open. 2019;2(11):e1914729–e1914729.
  • Madzima T, Vahabi M, Lofters A. Emerging role of HPV self-sampling in cervical cancer screening for hard-to-reach women. Can Family Physician. 2017;63:597–601.
  • Asciutto KC, Ernstson A, Foorslund O, et al. Self-sampling with HPV mRNA analyses from vagina and urine compared with cervical samples. J Clin Virol. 2018;101:69–73.
  • Sahasrabuddhe VV, Luhn P, Wentzensen N. Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts. Future Microbiol. 2011;6(9):1083–1098.
  • Aitken CA, van Agt HME, Siebers AG, et al. Introduction of primary screening using high-risk HPV DNA detection in the Dutch cervical cancer screening programme: a population-based cohort study. BMC Med. 2019;17(1):228–228. DOI:10.1186/s12916-019-1460-0.
  • Maver PJ, Poljak M, Primary HP. V-based cervical cancer screening in Europe: implementation status, challenges, and future plans. Clin Microbiol Infect. 2020;26(5):579–583.
  • Frayle H, Gori S, Rizzi M, et al. HPV testing for cervical cancer screening: technical improvement of laboratory logistics and good clinical performance of the cobas 6800 in comparison to the 4800 system. BMC Women’s Health. 2019;19(1):47. DOI:10.1186/s12905-019-0743-0.
  • Lindroth Y, Borgfeldt C, Thorn G, et al. Population-based primary HPV mRNA cervical screening compared with cytology screening. Prev Med. 2019;124:61–66.
  • Authority DH, Cancer Screening Fact Sheet, Denmark – cervix – 2017. 2017.
  • Sørbye SW, Fismen S, Gutteberg TJ, et al. Primary cervical cancer screening with an HPV mRNA test: a prospective cohort study. BMJ Open. 2016;6(8):e011981. DOI:10.1136/bmjopen-2016-011981.
  • Katki HA, Wacholder S, Solomon D, et al. Risk estimation for the next generation of prevention programmes for cervical cancer. Lancet Oncol. 2009;10(11):1022–1023. DOI:10.1016/S1470-2045(09)70253-0.
  • Tornesello ML, Buonaguro L, Giorgi-Rossi P, et al. Viral and cellular biomarkers in the diagnosis of cervical intraepithelial neoplasia and cancer. Biomed Res Int. 2013;2013:519619–519619.
  • Wentzensen N, Schiffman M, Palmer T, et al. Triage of HPV positive women in cervical cancer screening. J Clin Virol. 2016;76:S49–S55.
  • Godoy-Vitorino F, Romaguera J, Zhao C, et al. Cervicovaginal fungi and bacteria associated with cervical intraepithelial neoplasia and high-risk human papillomavirus infections in a hispanic population. Front Microbiol. 2018;9:2533.
  • Hudelist G, Manavi M, Pischinger KID, et al. Physical state and expression of HPV DNA in benign and dysplastic cervical tissue: different levels of viral integration are correlated with lesion grade. Gynecol Oncol. 2004;92(3):873–880. DOI:10.1016/j.ygyno.2003.11.035.
  • Wei WF, Su GD, Wu LF, et al. [Study of integrated state of HPV-16 infection in cervical cancer and precancerous tissues]. 2015;35(1):47–50.
  • Group TA-LTSA. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188(6):1383–1392.
  • Wright TC, Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197(4):346–355. DOI:10.1016/j.ajog.2007.07.047.
  • Siebers AG, Arbyn M, Melchers WJG, et al. Effectiveness of two strategies to follow-up ASC-US and LSIL screening results in The Netherlands using repeat cytology with or without additional hrHPV testing: a retrospective cohort study. Cancer Causes Control. 2014;25(9):1141–1149. (1573–7225 (Electronic)). DOI:10.1007/s10552-014-0414-2.
  • El-Zein M, Richardson L, Franco EL. Cervical cancer screening of HPV vaccinated populations: cytology, molecular testing, both or none. J Clin Virol. 2016;76:S62–S68.
  • Polman NJ, Snijders PJF, Kenter GG, et al. HPV-based cervical screening: rationale, expectations and future perspectives of the new Dutch screening programme. Prev Med. 2019;119:108–117.
  • Arbyn M, Smith SB, Temin S, et al. Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses. BMJ. 2018;363:k4823.
  • Kang L-N, Jeronimo J, Qiao Y-L, et al. Optimal positive cutoff points for careHPV testing of clinician- and self-collected specimens in primary cervical cancer screening: an analysis from Rural China. J Clin Microbiol. 2014;52(6):1954. DOI:10.1128/JCM.03432-13.
  • Zhao FH, Chen JF, Gao XH, et al. [Effectiveness and health economic analysis of strategies on cervical cancer screening and early diagnosis and treatment]. Zhonghua Zhong Liu Za Zhi. 2012;34(8):632–636.
  • Levin CE, Sellors J, Shi J-F, et al. Cost-effectiveness analysis of cervical cancer prevention based on a rapid human papillomavirus screening test in a high-risk region of China. Int J Cancer. 2010;127(6): 1404–1411. DOI:10.1002/ijc.25150. .
  • Kocken M, Uijterwaal MH, de Vries ALM, et al. High-risk human papillomavirus testing versus cytology in predicting post-treatment disease in women treated for high-grade cervical disease: a systematic review and meta-analysis. Gynecol Oncol. 2012;125(2):500–507. DOI:10.1016/j.ygyno.2012.01.015.
  • Vinokurova S, Wentzensen N, Kraus I, et al. Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res. 2008;68(1):307. DOI:10.1158/0008-5472.CAN-07-2754.
  • de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11(11):1048–1056. DOI:10.1016/S1470-2045(10)70230-8.
  • Gustavsson I, Sanner K, Lindell M, et al. Type-specific detection of high-risk human papillomavirus (HPV) in self-sampled cervicovaginal cells applied to FTA elute cartridge. J Clin Virol. 2011;51(4):255–258. DOI:10.1016/j.jcv.2011.05.006.
  • Ebisch RMF, de Kuyper-de Ridder GM, Bosgraaf RP, et al. The clinical value of HPV genotyping in triage of women with high-risk-HPV-positive self-samples. Int J Cancer. 2016;139(3):691–699. DOI:10.1002/ijc.30090.
  • Wright TC, Stoler MH, Behrens CM, et al. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e1-46.e11. DOI:10.1016/j.ajog.2011.07.024.
  • Castle PE, Fetterman B, Poitras N, et al. Five-year experience of human papillomavirus DNA and papanicolaou test cotesting. Obstetrics Gynecol. 2009;113(3):595–600. DOI:10.1097/AOG.0b013e3181996ffa.
  • Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007;297(8):813–819. DOI:10.1001/jama.297.8.813.
  • Xi LF, Hughes JP, Castle PE, et al. Viral load in the natural history of human papillomavirus type 16 infection: a nested case-control study. J Infect Dis. 2011;203(10):1425–1433. DOI:10.1093/infdis/jir049.
  • Kim J, Kim BK, Jeon D, et al. Type-specific viral load and physical state of HPV type 16, 18, and 58 as diagnostic biomarkers for high-grade squamous intraepithelial lesions or cervical cancer. Cancer Res Treat. 2020;52(2): 396–405. DOI:10.4143/crt.2019.152. .
  • Constandinou-Williams C, Collins SI, Roberts S, et al. Is human papillomavirus viral load a clinically useful predictive marker? A longitudinal study. Cancer Epidemiology Biomarkers & Prevention. 2010;19(3):832. DOI:10.1158/1055-9965.EPI-09-0838.
  • Berggrund M, Gustavsson I, Aarnio R, et al. HPV viral load in self-collected vaginal fluid samples as predictor for presence of cervical intraepithelial neoplasia. Virol J. 2019;16(1):146–146. DOI:10.1186/s12985-019-1253-2.
  • Halec G, Dondog B, Pawlita M, et al. Concordance of HPV load and HPV mRNA for 16 carcinogenic/possibly carcinogenic HPV types in paired smear/tissue cervical cancer specimens. Arch Virol. 2017;162(11):3313–3327. DOI:10.1007/s00705-017-3452-8.
  • Cao M, Wang Y, Wang D, et al. Increased high-risk human papillomavirus viral load is associated with immunosuppressed microenvironment and predicts a worse long-term survival in cervical cancer patients. Am J Clin Pathol. 2019;153(4):502–512. DOI:10.1093/ajcp/aqz186.
  • Wu Y, Chen Y, Li L, et al. Associations of high-risk HPV types and viral load with cervical cancer in China. J Clin Virol. 2006;35(3):264–269. DOI:10.1016/j.jcv.2005.07.011.
  • Lee SJ, Kim WY, Shim S-H, et al. Semi-quantitative HPV viral load in patients with ASC-US cytology: viral load correlates strongly with the presence of CIN but only weakly with its severity. Cytopathology. 2015;26(1):19–25. DOI:10.1111/cyt.12146.
  • Carcopino X, Henry M, Mancini J, et al. Significance of HPV 16 and 18 viral load quantitation in women referred for colposcopy. J Med Virol. 2012;84(2):306–313. DOI:10.1002/jmv.23190.
  • Schmitt M, Depuydt C, Benoy I, et al. Multiple human papillomavirus infections with high viral loads are associated with cervical lesions but do not differentiate grades of cervical abnormalities. J Clin Microbiol. 2013;51(5):1458–1464. DOI:10.1128/JCM.00087-13.
  • Boulet GAV, Benoy IH, Depuydt CE, et al. Human papillomavirus 16 load and E2/E6 ratio in HPV16-positive women: biomarkers for cervical intraepithelial neoplasia ≥2 in a liquid-based cytology setting? Cancer Epidemiology Biomarkers & Prevention. 2009;18(11):2992. DOI:10.1158/1055-9965.EPI-09-0025.
  • van den Heuvel CNAM, Loopik DL, Ebisch RMF, et al. RNA-based high-risk HPV genotyping and identification of high-risk HPV transcriptional activity in cervical tissues. Mod Pathol. 2020;33(4):748–757. DOI:10.1038/s41379-019-0369-7.
  • Tsakogiannis D, Kyriakopoulou Z, Ruether IGA, et al. Determination of human papillomavirus 16 physical status through E1/E6 and E2/E6 ratio analysis. J Med Microbiol. 2014;63(12):1716–1723. DOI:10.1099/jmm.0.076810-0.
  • Galarowicz B, Jach R, Kidzierska J, et al. The role of mRNA E6/E7 HPV high oncogenic risk expression in colposcopy of cervical intraepithelial neoplasia (CIN). Przegl Lek. 2012 ;69(9):651–657.
  • Fontecha N, Basaras M, Hernáez S, et al. Assessment of human papillomavirus E6/E7 oncogene expression as cervical disease biomarker. BMC Cancer. 2016;16(1):852–852. DOI:10.1186/s12885-016-2885-x.
  • Benevolo M, Vocaturo A, Caraceni D, et al. 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. 2011;49(7):2643. DOI:10.1128/JCM.02570-10.
  • Benevolo M, Terrenato I, Mottolese M, et al. Diagnostic and prognostic validity of the human papillomavirus E6/E7 mRNA test in cervical cytological samples of HC2-positive patients. Cancer Causes Control. 2011;22(6):869–875. DOI:10.1007/s10552-011-9757-0.
  • Duvlis S, Popovska-Jankovic K, Arsova ZS, et al. HPV E6/E7 mRNA versus HPV DNA biomarker in cervical cancer screening of a group of Macedonian women. J Med Virol. 2015;87(9):1578–1586. DOI:10.1002/jmv.24199.
  • Dabeski D, Duvlis S, Basheska N, et al. Comparison between HPV DNA testing and HPV E6/E7 MRNA testing in women with squamous cell abnormalities of the uterine cervix. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2019;40(1):51–58.
  • Cui M, Chan N, Liu M, et al. Clinical performance of roche cobas 4800 HPV Test. J Clin Microbiol. 2014;52(6):2210–2211. DOI:10.1128/JCM.00883-14.
  • Ge Y, Christensen P, Luna E, et al. Performance of Aptima and Cobas HPV testing platforms in detecting high-grade cervical dysplasia and cancer. Cancer Cytopathol. 2017;125(8):652–657. DOI:10.1002/cncy.21875.
  • Macedo ACL, Gonçalves JCN, Bavaresco DV, et al. Accuracy of mRNA HPV tests for triage of precursor lesions and cervical cancer: a systematic review and meta-analysis. J Oncol. 2019;2019:6935030. DOI:10.1155/2019/6935030
  • Stoler MH, Wright TC, Cuzick J, et al. APTIMA HPV assay performance in women with atypical squamous cells of undetermined significance cytology results. Am J Obstet Gynecol. 2013;208(2):144.e1-144.e8. DOI:10.1016/j.ajog.2012.12.003.
  • Bruno MT, Ferrara M, Fava V, et al. A prospective study of women with ASCUS or LSIL pap smears at baseline and HPV E6/E7 mRNA positive: a 3-year follow-up. Epidemiol Infect. 2018;146(5):612–618. DOI:10.1017/S0950268818000250.
  • Rijkaart DC, Heideman DAM, Coupe VMH, et al. High-risk human papillomavirus (hrHPV) E6/E7 mRNA testing by PreTect HPV-Proofer for detection of cervical high-grade intraepithelial neoplasia and cancer among hrHPV DNA-positive women with normal cytology. J Clin Microbiol. 2012;50(7):2390–2396. DOI:10.1128/JCM.06587-11.
  • Ting J, Mugo N, Kwatampora J, et al. High-risk human papillomavirus messenger RNA testing in physician- and self-collected specimens for cervical lesion detection in high-risk women, Kenya. Sex Transm Dis. 2013;40(7):7. DOI:10.1097/OLQ.0b013e31828e5a91.
  • Nieves L, Enerson CL, Belinson S, et al. Primary cervical cancer screening and triage using an mRNA human papillomavirus assay and visual inspection. Int J Gynecologic Cancer. 2013;23(3):513. DOI:10.1097/IGC.0b013e318280f3bc.
  • Discacciati MG, da Silva ID, Villa LL, et al. Prognostic value of DNA and mRNA e6/e7 of human papillomavirus in the evolution of cervical intraepithelial neoplasia grade 2. Biomark Insights. 2014;9:15–22.
  • Zummeren MV, Kremer WW, Leeman A, et al. HPV E4 expression and DNA hypermethylation of CADM1, MAL, and miR124-2 genes in cervical cancer and precursor lesions. Mod Pathol. 2018;31(12):1842–1850.
  • Griffin H, Wu Z, Marnane R, et al. E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease. PloS One. 2012;7(12):e49974–e49974. DOI:10.1371/journal.pone.0049974.
  • Krawczyk E, Suprynowicz FA, Liu X, et al. Koilocytosis: a cooperative interaction between the human papillomavirus E5 and E6 oncoproteins. Am J Pathol. 2008;173(3):682–688. DOI:10.2353/ajpath.2008.080280.
  • Alves de Sousa NL, Alves RR, Martins MR, et al. Cytopathic effects of human papillomavirus infection and the severity of cervical intraepithelial neoplasia: a frequency study. Diagn Cytopathol. 2012;40(10):871–875.
  • Siebers AG, van der Linden H, Vedder JEM, et al. Presence of koilocytosis in low-grade smears of high-risk HPV-positive women is a negative predictor for cervical intraepithelial neoplasia grade 3 or more. Cytopathology. 2018;29(3):275–280. DOI:10.1111/cyt.12536.
  • Vrdoljak-Mozetič D, Krašević M, Verša Ostojić D, et al. HPV16 genotype, p16/Ki-67 dual staining and koilocytic morphology as potential predictors of the clinical outcome for cervical low-grade squamous intraepithelial lesions. Cytopathology. 2015;26(1):10–18. DOI:10.1111/cyt.12121.
  • Wentzensen N, Sun C, Ghosh A, et al. Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3. J Natl Cancer Inst. 2012;104(22):1738–1749. DOI:10.1093/jnci/djs425.
  • Leeman A, Jenkins D, Marra E, et al. Grading immunohistochemical markers p16 INK4a and HPV E4 identifies productive and transforming lesions caused by low- and high-risk HPV within high-grade anal squamous intraepithelial lesions. Br J Dermatol. 2020;182(4):1026–1033. DOI:10.1111/bjd.18342.
  • Leeman AA-O, Jenkins D, Pino M, et al. Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124-2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions. Cancer Med. 2020;9(7):2454–2461. (2045–7634 (Electronic)). DOI:10.1002/cam4.2855.
  • Hsu Y-W, Huang R-L, Su P-H, et al. Genotype-specific methylation of HPV in cervical intraepithelial neoplasia. J Gynecol Oncol. 2017;28(4). DOI:10.3802/jgo.2017.28.e56.
  • Vinokurova S, von Knebel Doeberitz M, Ramqvist T. Differential methylation of the HPV 16 upstream regulatory region during epithelial differentiation and neoplastic transformation. PloS One. 2011;6(9):e24451–e24451.
  • Clarke MA, Wentzensen N, Mirabello L, et al. Human papillomavirus DNA methylation as a potential biomarker for cervical cancer. Cancer Epidemiology Biomarkers & Prevention. 2012;21(12):2125. DOI:10.1158/1055-9965.EPI-12-0905.
  • Kalantari M, Osann K, Calleja-Macias IE, et al. Methylation of human papillomavirus 16, 18, 31, and 45 L2 and L1 genes and the cellular DAPK gene: considerations for use as biomarkers of the progression of cervical neoplasia. Virology. 2014;448:314–321.
  • Amaro-Filho SM, Pereira Chaves CB, Felix SP, et al. HPV DNA methylation at the early promoter and E1/E2 integrity: a comparison between HPV16, HPV18 and HPV45 in cervical cancer. Papillomavirus Res. 2018;5:172–179.
  • Clarke MA, Gradissimo A, Schiffman M, et al. Human papillomavirus DNA methylation as a biomarker for cervical precancer: consistency across 12 genotypes and potential impact on management of HPV-positive women. Clin Cancer Res off J Am Assoc Cancer Res. 2018;24(9):2194–2202. DOI:10.1158/1078-0432.CCR-17-3251.
  • Woodman CB, Collins Si Fau - Young LS, Young LS. The natural history of cervical HPV infection: unresolved issues. Nature Reviews Cancer. 2007;7(1):11–22. DOI:10.1038/nrc2050. (1474-175X (Print))
  • Nam EJ, Kim JW, Hong JW, et al. Expression of the p16 and Ki-67 in relation to the grade of cervical intraepithelial neoplasia and high-risk human papillomavirus infection. J Gynecol Oncol. 2008;19(3):162–168. DOI:10.3802/jgo.2008.19.3.162.
  • Romagosa C, Simonetti S, López-Vicente L, et al. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30(18):2087–2097.
  • Carozzi F, Gillio-Tos A, Confortini M, et al. Risk of high-grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial. Lancet Oncol. 2013;14(2):168–176. DOI:10.1016/S1470-2045(12)70529-6.
  • Yang QC, Zhu Y, Liou H-B, et al. A cocktail of MCM2 and TOP2A, p16INK4a and Ki-67 as biomarkers for the improved diagnosis of cervical intraepithelial lesion. Pol J Pathol. 2013;64(1):21–27. DOI:10.5114/pjp.2013.34599.
  • Zeng W-J, Li Y, Fei H-L, et al. The value of p16ink4a expression by fluorescence in situ hybridization in triage for high risk HPV positive in cervical cancer screening. Gynecol Oncol. 2011;120(1):84–88. DOI:10.1016/j.ygyno.2010.09.008.
  • Mendaza S, Fernández-Irigoyen J, Santamaría E, et al. Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix. Int J Mol Sci. 2020;21(6): 2125. DOI:10.3390/ijms21062125. .
  • Group R Improving consistency in the diagnosis of cervical pre-cancers: roche CINtec Histology test receives FDA clearance. 2017 April 5 [cited 2020 May 5]; Available from: https://www.roche.com/dam/jcr:37a72ad4-c338-4be9-b6d6-79147a9c0029/en/med-cor-2017-04-05-e.pdf
  • Schmidt D, Bergeron C, Denton KJ, et al. p16/ki-67 dual-stain cytology in the triage of ASCUS and LSIL papanicolaou cytology. Cancer Cytopathol. 2011;119(3):158–166. DOI:10.1002/cncy.20140.
  • Lin J, Albers AE, Qin J, et al. Prognostic significance of overexpressed p16INK4a in patients with cervical cancer: a meta-analysis. PloS One. 2014;9(9):e106384–e106384. DOI:10.1371/journal.pone.0106384.
  • Milde-Langosch K, Bamberger A-M, Rieck G, et al. Overexpression of the p16 cell cycle inhibitor in breast cancer is associated with a more malignant phenotype. Breast Cancer Res Treat. 2001;67(1):61–70. DOI:10.1023/A:1010623308275.
  • Dai CY, Furth EE, Mick R, et al. p16(INK4a) expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation. Gastroenterology. 2000;119(4):929–942. DOI:10.1053/gast.2000.17952.
  • Guida M, Sanguedolce F, Bufo PA, et al. Aberrant DNA hypermethylation of hMLH-1 and CDKN2A/p16 genes in benign, premalignant and malignant endometrial lesions. Eur J Gynaecol Oncol. 2009;30(3):267–270.
  • Romagosa C, Simonetti S, López-Vicente L, et al. p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30(18):2087–2097.
  • Schwartz B, Avivi-Green C Fau - Polak-Charcon S, Polak-Charcon S. Sodium butyrate induces retinoblastoma protein dephosphorylation, p16 expression and growth arrest of colon cancer cells. Mol Cell Biochem. 1998;188(1/2):21–30. (0300–8177 (Print)). DOI:10.1023/A:1006831330340.
  • Inoue K, Fry EA. Aberrant expression of p16(INK4a) in human cancers - a new biomarker? Cancer Rep Rev. 2018;2(2). DOI:10.15761/CRR.1000145
  • Suman S, Mishra A. An interaction network driven approach for identifying biomarkers for progressing cervical intraepithelial neoplasia. Sci Rep. 2018;8(1):12927.
  • Dixon EP, King LM, Nelson R, et al. Characterization and clinical validation of MCM2 and TOP2A monoclonal antibodies in the BD ProEx™ C assay: an immunoassay which detects aberrant S-phase induction in cervical tissue. J Immunol Methods. 2017;442:35–41.
  • Wang FL, Yang Y, Liu ZY, et al. Correlation between methylation of the p16 promoter and cervical cancer incidence. Eur Rev Med Pharmacol Sci. 2017;21(10):2351–2356.
  • Jeong DH, Youm MY, Kim YN, et al. Promoter methylation of p16, DAPK, CDH1, and TIMP-3 genes in cervical cancer: correlation with clinicopathologic characteristics. Int J Gynecological Cancer. 2006;16(3):1234–1240. DOI:10.1136/ijgc-00009577-200605000-00043.
  • Jha AK, NIKBAKHT M, JAIN V, et al. p16INK4a and p15INK4b gene promoter methylation in cervical cancer patients. Oncol Lett. 2012;3(6):1331–1335. DOI:10.3892/ol.2012.655.
  • Carestiato FN, Amaro-Filho SM, Moreira MA, et al. Methylation of p16 ink4a promoter is independent of human papillomavirus DNA physical state: a comparison between cervical pre-neoplastic and neoplastic samples. Memórias Inst Oswaldo Cruz. 2019;114:e180456.
  • Li RN, Li C-Y, Lee C-H, et al. Promoter methylation status of the tumor suppressor genes p16 and cadherin 1 in cervical intraepithelial neoplasia. Oncol Lett. 2017;13(6):4397–4401. DOI:10.3892/ol.2017.5975.
  • Chakraborty C, Roychowdhury A, Samadder S, et al. Association of P16-RBSP3 inactivation with phosphorylated RB1 overexpression in basal–parabasal layers of normal cervix unchanged during CACX development. Biochem J. 2016;473(19):3221–3236. DOI:10.1042/BCJ20160323.
  • Tsakogiannis D, Moschonas GD, Bella E, et al. Association of p16 (CDKN2A) polymorphisms with the development of HPV16-related precancerous lesions and cervical cancer in the Greek population. J Med Virol. 2018;90(5):965–971. DOI:10.1002/jmv.24996.
  • Thakur N, Hussain S, Nasare V, et al. Association analysis of p16 (CDKN2A) and RB1 polymorphisms with susceptibility to cervical cancer in Indian population. Mol Biol Rep. 2012;39(1):407–414. DOI:10.1007/s11033-011-0752-z.
  • van Zummeren M, Leeman A, Kremer WW, et al. Three-tiered score for Ki-67 and p16 ink4a improves accuracy and reproducibility of grading CIN lesions. J Clin Pathol. 2018;71(11):981–988. DOI:10.1136/jclinpath-2018-205271.
  • Peres AL, Paz E Silva KM, de Araújo RFF, et al. Immunocytochemical study of TOP2A and Ki-67 in cervical smears from women under routine gynecological care. J Biomed Sci. 2016;23(1):42. DOI:10.1186/s12929-016-0258-z.
  • Tjalma WAA. Diagnostic performance of dual-staining cytology for cervical cancer screening: a systematic literature review. Eur J Obstet Gynecol Reprod Biol. 2017;210:275–280.
  • Reuschenbach M, Seiz M, Doeberitz CVK, et al. Evaluation of cervical cone biopsies for coexpression of p16INK4a and Ki-67 in epithelial cells. International Journal of Cancer. 2012;130(2):388–394. (1097–0215 (Electronic)). DOI:10.1002/ijc.26017.
  • Gustinucci D, Rossi PG, Cesarini E, et al. Use of cytology, E6/E7 mRNA, and p16 INK4a–Ki-67 to define the management of human papillomavirus (HPV)–positive women in cervical cancer screening. Am J Clin Pathol. 2016;145(1):35–45. DOI:10.1093/ajcp/aqv019.
  • Litjens R, Hopman AH, van de Vijiver KK, et al. Molecular biomarkers in cervical cancer diagnosis: a critical appraisal. Expert Opin Med Diagn. 2013;7(4):365–377.
  • Peeters E, Wentzensen N, Bergeron C, et al. Meta-analysis of the accuracy of p16 or p16/Ki-67 immunocytochemistry versus HPV testing for the detection of CIN2+/CIN3+ in triage of women with minor abnormal cytology. Cancer Cytopathol. 2019;127(3):169–180. DOI:10.1002/cncy.22103.
  • Ebisch RM, van der Horst J, Hermsen M, et al. Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women. Mod Pathol. 2017;30(7):1021–1031. DOI:10.1038/modpathol.2017.16.
  • Gonzalez MA, Tachibana K-EK, Laskey RA, et al. Control of DNA replication and its potential clinical exploitation. Nat Rev Cancer. 2005;5(2):135–141. DOI:10.1038/nrc1548.
  • Zheng J. Diagnostic value of MCM2 immunocytochemical staining in cervical lesions and its relationship with HPV infection. Int J Clin Exp Pathol. 2015;8(1):875–880.
  • Ratnam S, Coutlee F, Fontaine D, et al. Clinical performance of the PreTect HPV-Proofer E6/E7 mRNA assay in comparison with that of the Hybrid Capture 2 test for identification of women at risk of cervical cancer. Journal of Clinical Microbiology. 2010;48(8):2779–2785. (1098-660X (Electronic)). DOI:10.1128/JCM.00382-10.
  • Alaghehbandan R, Fontaine D, Bentley J, et al. Performance of proex c and pretect hpv-proofer e6/e7 mrna tests in comparison with the hybrid capture 2 hpv dna test for triaging ascus and lsil cytology. Diagn Cytopathol. 2013;41(9):767–775. DOI:10.1002/dc.22944.
  • Ding L, Song L, Zhao W, et al. Predictive value of p16INK4a, Ki-67 and ProExC immuno‑qualitative features in LSIL progression into HSIL. Exp Ther Med. 2020;19(4):2457–2466.
  • Amaro Filho SM, Nuovo GJ, Cunha CB, et al. Correlation of MCM2 detection with stage and virology of cervical cancer. Int J Biol Markers. 2014;29(4):e363–71. DOI:10.5301/jbm.5000081.
  • Tang X, Xu Y, Lu L, et al. Identification of key candidate genes and small molecule drugs in cervical cancer by bioinformatics strategy. Cancer Management and Research. 2018;Volume 10:3533–3549. (1179–1322 (Print)). DOI: 10.2147/CMAR.S171661.
  • Thomas LK, Bermejo JL, Vinokurova S, et al. Chromosomal gains and losses in human papillomavirus-associated neoplasia of the lower genital tract - a systematic review and meta-analysis. Eur J Cancer. 2014;50(1):85–98. DOI:10.1016/j.ejca.2013.08.022.
  • Seppo A, Jalali GR, Babkowski R, et al. Gain of 3q26: a genetic marker in low-grade squamous intraepithelial lesions (LSIL) of the uterine cervix. Gynecol Oncol. 2009;114(1):80–83. DOI:10.1016/j.ygyno.2009.03.031.
  • Koeneman MM, Ovestad IT, Janssen EAM, et al. Gain of chromosomal region 3q26 as a prognostic biomarker for high-grade cervical intraepithelial neoplasia: literature overview and pilot study. Pathol Oncol Res. 2019;25(2):549–557. DOI:10.1007/s12253-018-0480-y.
  • Wright TC, Compagno J, Romano P, et al. Amplification of the 3q chromosomal region as a specific marker in cervical cancer. Am J Obstet Gynecol. 2015;213(1):51 e1–51 e8. DOI:10.1016/j.ajog.2015.02.001.
  • Sokolova I, Algeciras-Schimnich A, Song M, et al. Chromosomal biomarkers for detection of human papillomavirus associated genomic instability in epithelial cells of cervical cytology specimens. J Mol Diagn. 2007;9(5):604–611. DOI:10.2353/jmoldx.2007.070007.
  • Heitmann ER, Lankachandra KM, Wall J, et al. 3q26 amplification is an effective negative triage test for LSIL: a historical prospective study. Plos One. 2012;7(7):e39101. DOI:10.1371/journal.pone.0039101.
  • Lin WM, Michalopulos EA, Dhurander N, et al. Allelic loss and microsatellite alterations of chromosome 3p14.2 are more frequent in recurrent cervical dysplasias. Clin Cancer Res. 2000;6(4):1410.
  • Harima Y, Harima K, Sawada S, et al. Loss of heterozygosity on chromosome 6p21.2 as a potential marker for recurrence after radiotherapy of human cervical cancer. Clin Cancer Res. 2000;6(3):1079.
  • Arias-Pulido H, Joste N, Wheeler CM. Loss of heterozygosity on chromosome 6 in HPV-16 positive cervical carcinomas carrying the DRB1*1501-DQB1*0602 haplotype. Genes Chromosomes Cancer. 2004;40(4):277–284.
  • Mazurenko Nn Fau - Bliev AI, Bliyev AY, Bidzhieva BA, et al. [Loss of heterozygosity at chromosome 6 as a marker of early genetic alterations in cervical intraepithelial neoplasias and microinvasive carcinomas]. Mol Biol (Mosk). 2006;40(3):385–395. (0026–8984 (Print)). DOI:10.1134/S0026893306030058.
  • Chambuso R, Kaambo E, Denny L, et al. Investigation of cervical tumor biopsies for chromosomal loss of heterozygosity (LOH) and microsatellite instability (MSI) at the HLA II Locus in HIV-1/HPV Co-infected Women. Front Oncol. 2019;9:951–951.
  • Beiersdorf J, Scheungraber C, Wunsch K, et al. Combined assessment of 3q26 amplification and promoter methylation in patients with high grade cervical lesions show age specific differences. Genes Chromosomes Cancer. 2020;59(3):168–177. DOI:10.1002/gcc.22818.
  • Xu W, Xu M, Wang L, et al. Integrative analysis of DNA methylation and gene expression identified cervical cancer-specific diagnostic biomarkers. Signal Transduct Target Ther. 2019;4(1):55. DOI:10.1038/s41392-019-0081-6.
  • Steenbergen RD, Snijders PJF, Heideman DAM, et al. Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions. Nat Rev Cancer. 2014;14(6):395–405. DOI:10.1038/nrc3728.
  • Lorincz AT. Virtues and weaknesses of DNA methylation as a test for cervical cancer prevention. Acta Cytol. 2016;60(6):501–512.
  • Lai HC, Ou Y-C, Chen T-C, et al. PAX1/ SOX1 DNA methylation and cervical neoplasia detection: a taiwanese gynecologic oncology group (TGOG) study. Cancer Med. 2014;3(4):1062–1074. DOI:10.1002/cam4.253.
  • Su P-H, Lai H-C, Huang R-L, et al. Paired box-1 (PAX1) activates multiple phosphatases and inhibits kinase cascades in cervical cancer. Sci Rep. 2019;9(1):9195. DOI:10.1038/s41598-019-45477-5.
  • Verhoef VM, Heideman DAM, van Kemenade FJ, et al. Methylation marker analysis and HPV16/18 genotyping in high-risk HPV positive self-sampled specimens to identify women with high grade CIN or cervical cancer. Gynecol Oncol. 2014;135(1):58–63. DOI:10.1016/j.ygyno.2014.08.003.
  • Leeman A, Ebisch RMF, Kasius A, et al. Defining hrHPV genotypes in cervical intraepithelial neoplasia by laser capture microdissection supports reflex triage of self-samples using HPV16/18 and FAM19A4/miR124-2 methylation. Gynecol Oncol. 2018;151(2):311–318. DOI:10.1016/j.ygyno.2018.09.006.
  • Vink FJA-OHOO, Meijer CJLM, Clifford GM, et al. FAM19A4/miR124-2 methylation in invasive cervical cancer: a retrospective cross-sectional worldwide study. International Journal of Cancer. 2020;147(4):1215–1221. (1097–0215 (Electronic)). DOI:10.1002/ijc.32614.
  • Qiagen. QIAGEN launches qiasure methylation test to determine cervical cancer risk. 2016 [cited 2020 May 10]; Available from: https://corporate.qiagen.com/newsroom/press-releases/2016/20160614-qiasure
  • De Strooper LMA, Verhoef VMJ, Berkhof J, et al. Validation of the FAM19A4/mir124-2 DNA methylation test for both lavage- and brush-based self-samples to detect cervical (pre)cancer in HPV-positive women. Gynecol Oncol. 2016;141(2):341–347. DOI:10.1016/j.ygyno.2016.02.012.
  • Kelly H, Benavente Y, Pavon MA, et al. Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis. Br J Cancer. 2019;121(11):954–965. DOI:10.1038/s41416-019-0593-4.
  • Verhoef VMJ, van Kemenade FJ, Rozendaal L, et al. Follow-up of high-risk HPV positive women by combined cytology and bi-marker CADM1/MAL methylation analysis on cervical scrapes. Gynecol Oncol. 2015;137(1):55–59. DOI:10.1016/j.ygyno.2015.01.550.
  • Bu Q, Wang S, Ma J, et al. The clinical significance of FAM19A4 methylation in high-risk HPV-positive cervical samples for the detection of cervical (pre)cancer in Chinese women. BMC Cancer. 2018;18(1):1182. DOI:10.1186/s12885-018-4877-5.
  • Dankai W, Khunamornpong S, Siriaunkgul S, et al. Role of genomic DNA methylation in detection of cytologic and histologic abnormalities in high risk HPV-infected women. Plos One. 2019;14(1):e0210289. DOI:10.1371/journal.pone.0210289.
  • Verlaat W, Snoek BC, Heideman DAM, et al. Identification and validation of a 3-gene methylation classifier for HPV-based cervical screening on self-samples. Clin Cancer Res off J Am Assoc Cancer Res. 2018;24(14):3456–3464. DOI:10.1158/1078-0432.CCR-17-3615.
  • Verhoef VMJ, Bosgraaf RP, van Kemenade FJ, et al. Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3): a randomised controlled non-inferiority trial. Lancet Oncol. 2014;15(3):315–322. DOI:10.1016/S1470-2045(14)70019-1.
  • Banno K, Iida M, Yanokura M, et al. MicroRNA in cervical cancer: oncomiRs and tumor suppressor miRs in diagnosis and treatment. ScientificWorldJournal. 2014;2014:178075.
  • Pardini B, De Maria D, Francavilla A, et al. MicroRNAs as markers of progression in cervical cancer: a systematic review. BMC Cancer. 2018;18(1):696. DOI:10.1186/s12885-018-4590-4.
  • Snoek BC, Verlaat W, Babion I, et al. Genome-wide microRNA analysis of HPV-positive self-samples yields novel triage markers for early detection of cervical cancer. International Journal of Cancer. 2019;144(2):372–379. (1097–0215 (Electronic)). DOI:10.1002/ijc.31855.
  • Ye J, Cheng X-D, Cheng B, et al. MiRNA detection in cervical exfoliated cells for missed high-grade lesions in women with LSIL/CIN1 diagnosis after colposcopy-guided biopsy. BMC Cancer. 2019;19(1):112. DOI:10.1186/s12885-019-5311-3.
  • Okoye JO, Ngokere AA, Onyenekwe CC, et al. Comparable expression of miR-let-7b, miR-21, miR-182, miR-145, and p53 in serum and cervical cells: diagnostic implications for early detection of cervical lesions. Int J Health Sci (Qassim). 2019;13(4):29–38.
  • Asangani IA, Rasheed SAK, Nikolova DA, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27(15):2128–2136. DOI:10.1038/sj.onc.1210856.
  • Lao G, Liu P, Wu Q, et al. Mir-155 promotes cervical cancer cell proliferation through suppression of its target gene LKB1. Tumour Biol. 2014;35(12):11933–11938. DOI:10.1007/s13277-014-2479-7.
  • Park S, Eom K, Kim J, et al. MiR-9, miR-21, and miR-155 as potential biomarkers for HPV positive and negative cervical cancer. BMC Cancer. 2017;17(1):658. DOI:10.1186/s12885-017-3642-5.
  • Group R, Roche wins the first HPV primary screening tender in Europe. 2015.
  • FDA. P890064/S009. Digene hybrid capture® 2 (HC2) high-risk HPV DNA test 2003 [cited 2020 May 1]; Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf/p890064s009a.pdf
  • FDA. P080015. CERVISTA HPV 16/18. 2009 [cited 2020 May 1]; Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf8/P080015a.pdf
  • FDA. P160037. BD Onclarity HPV Assay. 2018 [cited 2020 July 15]; Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160037a.pdf
  • FDA. P100020. cobas HPV test. 2011. [[cited 2020 May 1]]. Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf10/p100020a.pdf
  • FDA. P100042. APTIMA HPV assay. 2011. [[cited 2020 May 1]]. Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf10/p100042a.pdf
  • Carozzi F, Visioli CB, Confortini M, et al. hr-HPV testing in the follow-up of women with cytological abnormalities and negative colposcopy. Br J Cancer. 2013;109(7):1766–1774. DOI:10.1038/bjc.2013.519.
  • Kudela E, Farkasova A, Visnovsky J, et al. Amplification of 3q26 and 5p15 regions in cervical intraepithelial neoplasia. Acta Obstet Gynecol Scand. 2014;93(10):997–1002. DOI:10.1111/aogs.12485.
  • Jiang Y, Hu Z, Zuo Z, et al. Identification of circulating MicroRNAs as a promising diagnostic biomarker for cervical intraepithelial neoplasia and early cancer: a meta-analysis. Biomed Res Int. 2020;2020:4947381.
  • Jin Y, Kim SC, Kim HJ, et al. Use of protein-based biomarkers of exfoliated cervical cells for primary screening of cervical cancer. Arch Pharm Res. 2018;41(4):438–449. DOI:10.1007/s12272-018-1015-5.
  • Kontostathi G, Zoidakis J, Anagnou NP, et al. Proteomics approaches in cervical cancer: focus on the discovery of biomarkers for diagnosis and drug treatment monitoring. Expert Rev Proteomics. 2016;13(8):731–745. (1744–8387 (Electronic)). DOI:10.1080/14789450.2016.1210514.
  • Benczik M, Galamb Á, Koiss R, et al. Claudin-1 as a biomarker of cervical cytology and histology. Pathol Oncol Res. 2016;22(1):179–188. (0253–6269 (Print)). DOI:10.1007/s12253-015-9990-z.
  • Zacapala-Gómez AE, Navarro-Tito N, Alarcón-Romero LDC, et al. Ezrin and E-cadherin expression profile in cervical cytology: a prognostic marker for tumor progression in cervical cancer. BMC Cancer. 2018;18(1):349. DOI:10.1186/s12885-018-4243-7.
  • Mohammed SI, Ren W, Flowers L, et al. Point-of-care test for cervical cancer in LMICs. Oncotarget. 2016;7(14):18787–18797. DOI:10.18632/oncotarget.7709.
  • Usyk M, Zolnik CP, Castle PE, et al. Cervicovaginal microbiome and natural history of HPV in a longitudinal study. PLoS Pathog. 2020;16(3):e1008376. DOI:10.1371/journal.ppat.1008376.
  • Oh HY, Kim B-S, Seo -S-S, et al. The association of uterine cervical microbiota with an increased risk for cervical intraepithelial neoplasia in Korea. Clin Microbiol Infect. 2015;21(7):674.e1-674.e9. DOI:10.1016/j.cmi.2015.02.026.
  • Curty G, Costa RL, Siqueira JD, et al. Analysis of the cervical microbiome and potential biomarkers from postpartum HIV-positive women displaying cervical intraepithelial lesions. Sci Rep. 2017;7(1):17364. DOI:10.1038/s41598-017-17351-9.