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Claudin-1 as a Biomarker of Cervical Cytology and Histology

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Pathology & Oncology Research

Abstract

Several immunochemistry tests are used for triaging human papilloma virus (HPV) and cytology positive cases in cervical cancer screening and as an adjunct test to diagnose cervical cancer. Claudin-1 (CLDN1) protein is a major component of the tight junction, shown to have altered expression in cervical cancer. In this study, value of CLDN1 was analysed as a screening and triage immunochemistry test compared to cytology and HPV testing. A population of 352 women attending colposcopic referral visits resulting in cervical conisation and a second population of 150 women attending routine gynaecological visits with negative cervical cytology were enrolled in a multi-centre clinical study in Hungary. Cytology and HPV (Genoid Full Spectrum HPV Amplification and Detection System) testing were carried out along with immunocytochemistry for CLDN1, and as a reference, using CINtec p16 Cytology Kit. Three different evaluation protocols were used which assessed immunostaining characteristics with or without cytological readings. High correlation observable between p16INK4a and CLDN1 established CLDN1 as a competing marker in cervical cancer. Concordance of CLDN1 immunostaining of cervical intraepithelial neoplasia 2 and above (CIN2+) positives was 84.0 % (73.8–89.3); concordance of CIN2+ negatives was 69.0 % (59.6–75.8). In conclusion, CLDN1 has similar diagnostic potential as p16INK4a, our results established it as a histological and cytological biomarker with the potential to improve the clinical performance of cervical cytology and histology.

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References

  1. Forouzanfar MH, Foreman KJ, Delossantos AM, et al. (2011) Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet 378:1461–1484. doi:10.1016/S0140-6736(11)61351-2

    Article  PubMed  Google Scholar 

  2. Iarc (2003) Colposcopy and treatment of cervical intraepithelial neoplasia: A beginners' manual. 1–132.

  3. Wright TC, Massad LS, Dunton CJ, et al. (2007) 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 197:346–355. doi:10.1016/j.ajog.2007.07.047

    Article  PubMed  Google Scholar 

  4. Gustafsson L, Pontén J, Bergström R, Adami HO (1997) International incidence rates of invasive cervical cancer before cytological screening. Int J Cancer 71:159–165

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Cuzick J, Clavel C, Petry K-U, et al. (2006) Overview of the European and north American studies on HPV testing in primary cervical cancer screening. Int J Cancer 119:1095–1101. doi:10.1002/ijc.21955

    Article  CAS  PubMed  Google Scholar 

  7. 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 11:249–257. doi:10.1016/S1470-2045(09)70360-2

    Article  CAS  PubMed  Google Scholar 

  8. Anttila A, Kotaniemi-Talonen L, Leinonen M, et al. (2010) Rate of cervical cancer, severe intraepithelial neoplasia, and adenocarcinoma in situ in primary HPV DNA screening with cytology triage: randomised study within organised screening programme. BMJ 340:c1804

    Article  PubMed Central  PubMed  Google Scholar 

  9. Plummer M, Schiffman M, Castle PE, et al. (2007) A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis 195:1582–1589. doi:10.1086/516784

    Article  PubMed  Google Scholar 

  10. Rodríguez AC, Schiffman M, Herrero R, et al. (2008) Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 100:513–517. doi:10.1093/jnci/djn044

    Article  PubMed Central  PubMed  Google Scholar 

  11. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin 62:147–172. doi:10.3322/caac.21139

  12. Naucler P, Ryd W, Törnberg S, et al. (2009) Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst 101:88–99. doi:10.1093/jnci/djn444

    Article  PubMed  Google Scholar 

  13. Rijkaart DC, Berkhof J, van Kemenade FJ, et al. (2012) HPV DNA testing in population-based cervical screening (VUSA-screen study): results and implications. Br J Cancer 106:975–981. doi:10.1038/bjc.2011.581

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Castle PE, Stoler MH, Wright TC, et al. (2011) Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 12:880–890. doi:10.1016/S1470-2045(11)70188-7

    Article  PubMed  Google Scholar 

  15. Overmeer RM, Louwers JA, Meijer CJLM, et al. (2011) Combined CADM1 and MAL promoter methylation analysis to detect (pre-)malignant cervical lesions in high-risk HPV-positive women. Int J Cancer 129:2218–2225. doi:10.1002/ijc.25890

    Article  CAS  PubMed  Google Scholar 

  16. Depuydt CE, Makar AP, Ruymbeke MJ, et al. (2011) BD-ProExC as adjunct molecular marker for improved detection of CIN2+ after HPV primary screening. Cancer Epidemiol Biomark Prev 20:628–637. doi:10.1158/1055-9965.EPI-10-0818

    Article  CAS  Google Scholar 

  17. Patel DA, Rozek LS, Colacino JA, et al. (2012) Patterns of cellular and HPV 16 methylation as biomarkers for cervical neoplasia. J Virol Methods 184:84–92. doi:10.1016/j.jviromet.2012.05.022

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. De Strooper LMA, Hesselink AT, Berkhof J, et al. (2014) Combined CADM1/MAL methylation and cytology testing for colposcopy triage of high-risk HPV-positive women. Cancer Epidemiol Biomark Prev 23:1933–1937. doi:10.1158/1055-9965.EPI-14-0347

    Article  Google Scholar 

  19. Bibbo M, DeCecco J, Kovatich AJ (2003) P16INK4A as an adjunct test in liquid-based cytology. Anal Quant Cytol Histol 25:8–11

    PubMed  Google Scholar 

  20. Galamb Á, Benczik M, Zinner B, et al. (2015) Dysregulation of microRNA expression in human cervical preneoplastic and neoplastic lesions. Pathol Oncol Res. doi:10.1007/s12253-014-9871-x

    Google Scholar 

  21. Tsoumpou I, Arbyn M, Kyrgiou M, et al. (2009) p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev 35:210–220. doi:10.1016/j.ctrv.2008.10.005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Galgano MT, Castle PE, Atkins KA, et al. (2010) Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol 34:1077–1087. doi:10.1097/PAS.0b013e3181e8b2c4

    Article  PubMed Central  PubMed  Google Scholar 

  23. Denton KJ, Bergeron C, Klement P, et al. (2010) The sensitivity and specificity of p16(INK4a) cytology vs HPV testing for detecting high-grade cervical disease in the triage of ASC-US and LSIL pap cytology results. Am J Clin Pathol 134:12–21. doi:10.1309/AJCP3CD9YKYFJDQL

    Article  PubMed  Google Scholar 

  24. Van Bogaert L-J (2012) P16INK4a immunocytochemistry/immunohistochemistry: need for scoring uniformization to be clinically useful in gynecological pathology. Ann Diagn Pathol 16:422–426. doi:10.1016/j.anndiagpath.2012.03.006

    Article  PubMed  Google Scholar 

  25. Lal-Nag M, Morin PJ (2009) The claudins. Genome Biol 10:235. doi:10.1186/gb-2009-10-8-235

    Article  PubMed Central  PubMed  Google Scholar 

  26. Tsukita S, Yamazaki Y, Katsuno T, Tamura A (2008) Tight junction-based epithelial microenvironment and cell proliferation. Oncogene 27:6930–6938. doi:10.1038/onc.2008.344

    Article  CAS  PubMed  Google Scholar 

  27. Morin PJ (2005) Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 65:9603–9606. doi:10.1158/0008-5472.CAN-05-2782

    Article  CAS  PubMed  Google Scholar 

  28. Sobel G, Németh J, Kiss A, et al. (2006) Claudin 1 differentiates endometrioid and serous papillary endometrial adenocarcinoma. Gynecol Oncol 103:591–598. doi:10.1016/j.ygyno.2006.04.005

    Article  CAS  PubMed  Google Scholar 

  29. Sobel G, Páska C, Szabó I, et al. (2005) Increased expression of claudins in cervical squamous intraepithelial neoplasia and invasive carcinoma. Hum Pathol 36:162–169. doi:10.1016/j.humpath.2004.12.001

    Article  CAS  PubMed  Google Scholar 

  30. Szabó I, Kiss A, Schaff Z, Sobel G (2009) Claudins as diagnostic and prognostic markers in gynecological cancer. Histol Histopathol 24:1607–1615

    PubMed  Google Scholar 

  31. Lee J-W, Lee S-J, Seo J, et al. (2005) Increased expressions of claudin-1 and claudin-7 during the progression of cervical neoplasia. Gynecol Oncol 97:53–59. doi:10.1016/j.ygyno.2004.11.058

    Article  CAS  PubMed  Google Scholar 

  32. Wentzensen N, von Knebel DM (2007) Biomarkers in cervical cancer screening. Dis Markers 23:315–330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Tornesello ML, Buonaguro L, Giorgi-Rossi P, Buonaguro FM (2013) Viral and cellular biomarkers in the diagnosis of cervical intraepithelial neoplasia and cancer. Biomed Res Int 2013:519619. doi:10.1155/2013/519619

    Article  PubMed Central  PubMed  Google Scholar 

  34. Vázquez-Ortíz G, Ciudad CJ, Piña P, et al. Gene identification by cDNA arrays in HPV-positive cervical cancer. Arch Med Res 36:448–458. doi:10.1016/j.arcmed.2005.04.016

  35. Vrdoljak-Mozetič D, Krašević M, Verša Ostojić D, et al. (2015) 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 26:10–18. doi:10.1111/cyt.12121

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by FP7 Collaborative project Automatic Cancer Screening Based on Real-time PCR – AUTOCAST, #HEALTH-2007-2.4.1-4; NKFP_07_2-SPE-SAFE, Jedlik Ányos 2nd sub program #KMR_12-1-2012-0032 by the Hungarian National Research and Development Fund and by the Hungarian National Research Foundation #PD105019.

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Authors and Affiliations

  1. Cellcall Ltd., Röppentyű u. 48, Budapest, 1134, Hungary

    Márta Benczik, Attila Kovács & Csaba Jeney

  2. 2nd Department of Obstetrics and Gynecology, Semmelweis University, Üllői út 78/a, Budapest, 1082, Hungary

    Ádám Galamb & Gábor Sobel

  3. Combined Szent István and Szent László Hospital, Nagyvárad tér 1, Budapest, 1097, Hungary

    Róbert Koiss

  4. 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary

    Balázs Járay, Tamás Székely, Tímea Szekerczés & Zsuzsa Schaff

  5. Synlab Hungary Ltd., Bajcsy-Zsilinszky út 53, Budapest, 1065, Hungary

    Márta Benczik

  6. Department of Medical Microbiology, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary

    Csaba Jeney

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  1. Márta Benczik
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  2. Ádám Galamb
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Corresponding author

Correspondence to Csaba Jeney.

Additional information

Gábor Sobel and Csaba Jeney equally contributed.

Electronic supplementary material

12253_2015_9990_MOESM1_ESM.docx

Supplement Table 1 . Concordance of the immunostaining tests. Values are calculated for CIN2+ and CIN2- cases. Values <0.05 p indicate loss of concordance between the tests. (DOCX 26 kb)

12253_2015_9990_MOESM2_ESM.docx

Supplement Table 2. Sensitivity and specificity data of cytology (ASCUS+) and HPV (hr-HPV+) triage with different immunochemistry tests. For better comparison the table shows the results of the pooled population (PP) with the figures representing the whole study population and with values for the base test positive population only (TP). Immunochemistry was evaluated by two different protocols: SM: simple scoring method; MASM: morphological reading adjusted scoring method. Sensitivity and specificity data for the HPV and cytology triage are also shown. (DOCX 17 kb)

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Benczik, M., Galamb, Á., Koiss, R. et al. Claudin-1 as a Biomarker of Cervical Cytology and Histology. Pathol. Oncol. Res. 22, 179–188 (2016). https://doi.org/10.1007/s12253-015-9990-z

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  • DOI: https://doi.org/10.1007/s12253-015-9990-z

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