Molecular markers in cervical screening – a promise for the future

Open access


Cervical cancer is one of the leading cancers in women worldwide. The detection and diagnosis of cervical carcinoma and its precursor lesions, called cervical intraepithelial lesions (CIN), represents the main goal in order to decrease the morbidity and mortality of this disease. In the majority of cases CIN resolve spontaneously. Only a minor part of the lesions develop to high-grade lesions and eventually invasive cancer and it is important to detect those CIN with potential to progress to cervical cancer. For clinical management it is important to distinguish the cervical dysplasia with regression potential in order to avoid unnecessary treatments. Many potential biomarkers have been analyzed for the characterization of cervical cancer and pre-cancer. So far, detection of HPV has been the most promising clinical application. Several new markers have been evaluated intensively and might be used in some clinical settings, mainly p16, MCM5/CDC6 and HPV RNA, integration of HPV DNA into the host genome, chromosomal imbalances. In this article, representative examples of these markers are presented in the context of improved cervical disease detection and progression.

1. Ostor AG. Natural history of cervical intraephitelial neoplasia: a critical review. Int J Gynecol Pathol. 1993; 12(2):186-92

2. Davey E, Barrat A, Irwing L, Chan SF, Macaskill P, Mannes P. Effect of study design and quality on unsatisfactory rates, cytology classifications and accuracy in liquid- based versus conventional cervical cytology: a systematic review. Lancet. 2006; 367(9505):122-32

3. Confortini M, Bergeron C, Desai M, Negri G, Dalla Palma P, Montanari G, et al. Accuracy of liquid-based cytology: comparison of the results obtained within a randomized controlled trial (the New Technologies for Cervical Cancer Screening Study) and an external group of experts. Cancer Cytopathol. 2010 Aug 25;118(4):203-8.

4. Yim E-K, Park J-S. Biomarkers in Cervical Cancer. Biomark Insights. 2007 Feb 7;1:215-25.

5. von Knebel Doeberitz M. New markers for cervical dyspalsia to visualize the genomic chaos created by aberrant oncogenic papilomavirus infections. Eur J Cancer. 2002; 38(17):2229-42

6. Koskimaa HM, Kurvinen K, Costa S, Syrjanen K, Szrjanen S. Molecular markers implicating early malignant events in cervical carcinogenesis. Cancer Epidemiol Biomarkers Prev. 2010; 19(8)2003-12. Epub 2010 Jul 20

7. Malinowski D. Molecular diagnostic assays for cervical neoplasia: emerging markers for the detection of high-grade cervical disease. Biotechniques. 2005; Suppl: 17-23

8. zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000; 92(9):690-8

9. Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Hansson BG, et al. HPV type-specific risks of high-grade CIN during 4 years of follow-up: a population-based prospective study. Br. J. Cancer. 2007 Jul 2;97(1):129-32.

10. Moscicki AB, Shiboski S, Broering J. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998; 132:277-84

11. Goldie SJ, Grima D, Kohli M, Wright TC, Weinstein M, Franco E. A comprehensive natural history model of HPV infection and cervical cancer to estimate the clinical impact of a prophylactic HPV-16/18 vaccine. Int. J. Cancer. 2003 Oct 10;106(6):896-904.

12. Snidjers PJ, Steenbergen RD, Heideman DA, Meijer CJ. HPV mediated cervical carcinogenesis: conceps and clinical implications. J Pathol. 2006 Jan; 208(2):152-64

13. Wentzensen N, Vinokurova S, von Knebel Doeberitz M. Molecular markers of cervical squamous cell cancer precursor lesions. J Gynec Oncol. 2006; 11:30-40

14. Duensing S, Munger K. The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability. Cancer Res. 2002;62(23):7075-82

15. Melsheimer P, Vinokurova S, Wentzensen N, Bastert G, von Knebel Doeberitz M. DNA aneuploidy and integration of human papillomavirus type 16e7/e7 oncogenes in intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix uteri. Clin Cancer Res. 2004; 10(9)3059-63

16. Koliopoulos G, Valasoulis G, Zilakou E. An update review on HPV testing methods for cervical neoplasia. Expert Opinion on Medical Diagnostics. 2009;3(2):123-31.

17. Schiffman M, Wentzensen N, Wacholder S, Kinney W, Gage JC, Castle PE. Human papillomavirus testing in the prevention of cervical cancer. J. Natl. Cancer Inst. 2011 Mar 2;103(5):368-83.

18. Cuzick J, Szarewski A, Cubie H, Hulman G, Kitchener H, Luesley D. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet. 2003; 362(9399):1871-6.

19. Wetnzensen N, Vinokurova S, von Knebel Doeberitz M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female genital tract. Cancer Res.2004; 64(11): 3878-84

20. Pett M, Coleman N.Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol.2007; 212(4):356-67

21. Goel MM, Mehrotra A, Singh U, Gupta HP, Misra JS. MIB-1 and PCNA immunostaining as a diagnostic adjunct to cervical Pap smear. Diagn. Cytopathol. 2005 Jul;33(1):15-9.

22. Pirog EC, Baergen RN, Soslow RA, Tam D, DeMattia AE, Chen YT. Diagnostic accuracy of cervical low grade squamous intraephitelial lesions is improved with MIB-1 immunostaining. Am J Surg Pathol. 2002; 26(1):70-5

23. Brown CA, Bogers J, Sahebali S, Depuydt CE, De Prins F, Malinowski DP.Role of Protein Biomarkers in the Detection of High-Grade Disease in Cervical Cancer Screening Programs.J Oncol. 2012; 2012: 289315, doi:10.1155/2012/289315

24. Golijow CD, Abba MC, Mouron SA, Gomez MA, Dulout FN. C-myc gene amplification detected in preinvasive intraephitelial neoplasia. Int J Gynecol Cancer. 2001; 11(6):462-5

25. Klaes R, Friedrich T, Spitkovsy D, Ridder R., Rudy U, Petry G et al. Overexpression of p16ink4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer. 2001; 92:276-84

26. Sahebali S, Depuydt CE, Segers K, Moeneclay AJ, Vereecken AJ, Van Marck E, et al. P16INK4A as an adjunct marker inliquid-based cervical cytology. Int J Cancer. 2004; 108:871-6

27. Tringler B, Gup CJ, Singh M, Groshong S, Shroyer AL, Heinz DE et al. Evaluation of p16INK4A and pRB expression in cervical squamous and glandular neoplasia. Hum Pathol. 2004; 35:689-96

28. Schorge JO, Lea JS, Elias KJ, Rajanbabu R, Coleman RL, Miller DS et al. P16INK4A as a molecular biomarker of cervical adenocarcinoma. Am J Obstet Gynecol. 2004; 190:668

29. Passamonti B, Gustinucci D, Recchia P, Bulletti S, Carlani A, Cesarini E, et al. Expression of p16 in abnormal pap-tests as an indicator of CIN2+ lesions: a possible role in the low grade ASC/US and L/SIL (Ig) cytologic lesions for screening prevention of uterine cervical tumours. Pathologica. 2010; 102(1): 6-11

30. Sung CO, Kim SR, Oh YL, Song SY. The use of p16 (INK4A) immunocytochemistry in "Atypical squamous cells which cannot exclude HSIL" compared with "Atypical squamous cells of undetermined significance" in liquidbased cervical smears. Diag.Cytopathol. 2010; 38(3):168-71

31. Klaes R, Benner A, Freidrich T, Ridder R, Herrington S, Jenkins D. p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraephitelial neoplasia. Am J Surg Pathol.2002; 26(11):1389-99

32. Lee S, Kim H, Kim H, Kim C, Kim I.The Utility of p16INK4a and Ki-67 as a Conjunctive Tool in Uterine Cervical Lesions.Korean J Pathol. 2012 June; 46(3): 253-260

33. Ordi J, Garcia S, delPino M, Landolfi S, Alonso I, Quito L, et al.p16 INK4a immunostaining identifies occult CIN lesions in HPV-positive women. Int J Gynecol Pathol. 2009; 28(1):90-7.

34. Carozzi F, Cecchini S, Confortini M, Becattini V, Cariaggi MP, Pontenani G. Role of p16 expression in identifying CIN2 or more severe lesions among HPV-positive patients reffered for colposcopy after abnormal cytology. Cancer. 2006 Apr 25; 108(2):119-23

35. Tringler B, Gup CJ, Shroyer KR. Correlation between p16 and pRb expression in cervical squamous and glandular neoplasia. Human Pathol. 2004; 35:689-96

36. Branca M, Giorgi C, Santini D, Di Bonito L, Ciotti M, Costa S et al; HPV-Pathogen ISS Study Group. Survivin as a marker of cervical intraepithelial neoplasia and high-risk human papillomavirus and a predictor of virus clearance and prognosis in cervical cancer. Am J Clin Pathol. 2005 Jul;124(1):113-21

37. Lu D, Qian J, Yin X, Xiao Q, Wang C, Zeng Y. Expression of PTEN and survivin in cervical cancer: promising biological markers for early diagnosis and prognostic evaluation. Br J Biomed Sci. 2012;69(4):143-6.

38. Wu SF, Zhang JW, Qian WY, Yang YB, Liu Y, Dong Y et al. Altered expression of survivin, Fas and FasL contributed to cervical cancer development and metastasis. Eur Rev Med Pharmacol Sci. 2012 Dec;16(15):2044-50.

39. Ault KA, Allen HK, Phillips SL, Zimmerman MB, Klingelhitz AJ. Telomerase activity as a potential diagnostic marker for triage of abnormal Pap smears. J Low Genit Tract Dis. 2005; 9(2):93-9

40. Barbosa LC, da Silva ID, Correa JC, Ribalta JC. Survivin and telomerase expression in the uterine cervix of women with human papillomavirus-induced lesions. Int J Gynecol Cancer. 2011; 21(1):15-21

41. Tu Z, Zhang A, Wu R, Jiang J, Li Y, Wulan N et al. Genomic amplification of the human telomerase RNA gene for differential diagnosis of cervical disorders. Cancer Gent Cytogenet. 2009; 191(1):10-16

42. Porika M, Tippani R, Mohammad A, Bollam SR, Panuganti SD, Abbagani S. Evaluation of serum human telomerase reverse transcriptase as a novel marker for cervical cancer. Int J Biol Markers. 2011; 26(1):22-6

43. Samson SJ, Parker MR, Hessling JJ, Prpic DK, Hall L, Taylor AJ. Data comparison of three molecular markers (MCM7, p16 and integrin beta) for the detection of cervical dysplasia in SurePath cytology specimens.Acta Cytol.2004; 43:658

44. Dilinuer A, Azar A, Colgan T, Nanji S. A Pilot Evaluation of a Novel Immunohistochemical Assay for Topoisomerase II-α and Minichromosome Maintenance Protein 2 Expression (ProEx C) in Cervical Adenocarcinoma In Situ, Adenocarcinoma, and Benign Glandular Mimics. Int J Gynecol Pathol.2009;28(2):114-9

45. Sanati S, Huettner P, Ylagan LR. Role of ProExC: a novel immunoperoxidase marker in the evaluation of dysplastic squamous and glandular lesions in cervical specimens. Int J Gynecol Pathol.2010; 29(1):79-97

46. Baege AC, Disbrow GL, Schlegel R. IGFBP-3, a marker of cellular senescence, is overexpressed in human papillomavirus-immortalized cervical cells and enhances IGF-1 mitogenesis. J Virol.2004; 78:5720-7

47. Guo M, Baruch AC, Silva EG, Jan Yj, Lin S, Sneige N, et al. Efficacy of p16 and ProExC immunostaining in the detection of high-grade cervical intraepithelial neo- plasia and cervical carcinoma. Am J Clin Pathol.2011 feb; 135(2):211-20

48. Sanati S, Huettner P, Ylagan LR. Role of ProExC: a novel immunoperoxidase marker in the evaluation of dysplastic squamous and glandular lesions in cervical specimens. Int J Gynecol Pathol. 2010 Jan; 29(1):79-87.

49. Heselmeyer-Haddad K, Sommerfeld K, Schrock E, duMS, Blegen H, Shah K, Steinbeck R. Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. Proc Natl Acd Sci USA. 1996; 93(1):479-84

50. Vazquez-Mena O, Medina-Martinez I, Juarez-Torres E, Barron V, Espinosa A, Villegas-Sepulveda N. Amplified genes may be overexpressed, unchanged, or down regulated in Cervical Cancer Cell Lines. PLoS One. 2012; 7(3): e32667

51. Mathevet P, Frappart L, Hittelman W. [Cervix dysplasias: study of Rb and p53 gene expression and correlation with mitotic activity]. Gynecol Obstet Fertil. 2000 Jan;28(1):44-50.

52. Wentzensen N, Sherman NE, Schiffman M, Wang SS.Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science. Gynecol Oncol. 2009; 112(2):291-2

53. Yang N, Nijhuis ER, Volders HH, Eijsink JJ, Lendvai A, Zhang B, et al. Gene promoter methylation patterns throughout the process of cervical carcinogenesis. Cell Oncol. 2010; 32(1-2): 131-43.

54. Weaver EJ, Kovatich AJ, Bibbo M. Cyclin E expression and early cervical neoplasia in Thin Prep specimens. A feasability study. Acta Cytol. 2001; 25(7):884-91

55. El-Ghobashy AA, Shaaba AM, Herod J, Innes J, Prime W, Herrington CS. Overexpression of cyclins A and B as markers of neoplastic glandular lesions of the cervix uteri. Gynecol Oncol. 2004; 92:628-34

56. Obermair A, Bancher-Todesca D, Bilgi S, Kaider A, Kohlberger P, Müllauer-Ertl S et al. Correlation of vascular endothelial growth factor expression and microvessel density in cervical intraepithelial neoplasia. J Natl Cancer Inst. 1997 Aug 20;89(16):1212-7

57. Ozalp S, Yalcin OT, Oner U, Tanir HM, Acikalin M, Sarac I. Microvessel density as a prognostic factor in preinvasive and invasive cervical lesions. Eur J Gynaecol Oncol. 2003;24(5):425-8

58. Branca M, Giorgi C, Ciotti M, Santini D, Di Bonito L, Costa S et al; HPV-Pathogen Istituto Superiore di Sanità Study Group. Down-regulated nucleoside diphosphate kinase nm23-H1 expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer. J Clin Pathol. 2006 Oct;59(10):1044-51.

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2018: 0,800
5-year IMPACT FACTOR: 0,655

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2018: 0.194
Source Normalized Impact per Paper (SNIP) 2018: 0.306


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 257 161 20
PDF Downloads 102 80 5