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Predicting cervical intraepithelial neoplasia recurrence in HIV-infected and -noninfected women by detecting aberrant promoter methylation in the CDH1, TIMP3, and MGMT genes

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Aberrant DNA methylation is present in virtually all types of human cancer. There is no clear evidence that methylation status can predict bad prognosis in patients with CIN recurrence in HIV infected. This study evaluates the relationship between aberrant methylation of CpG islands of CDH1, TIMP3 and MGMT genes and CIN recurrence in HIV-infected and -noninfected women.

Methods

This is a nested case–control study involving 33 cases with CIN recurrence and 114 controls without recurrence, HIV infected and noninfected, treated with LEEP, between 1999 and 2004. Recurrence diagnosis was established after biopsy. Genes methylation profile was assessed by MSP-PCR technique in formalin-fixed, paraffin-embedded cone specimens. Statistical analysis was performed to compare categorical variables, using χ2 test with Yates correction and Fisher’s exact test. Multivariate analysis was carried out using logistic regression.

Results

CIN recurrence was more frequent in women with glandular involvement (OR 11.6; 95% CI 2.93–45.89) and compromised surgical margins (OR 2.5; 95% CI 0.87–7.27) in the cervical cone and in HIV-infected women (OR 2.47; 95% CI 0.87–7.05). One methylated allele of CDH1, TIMP3 and MGMT genes was present in 87.9% women with CIN recurrence. Promoter hypermethylation of TIMP3 and MGMT was detected in women with CIN recurrence and without CIN recurrence independent of HIV infection with significant difference between groups (p = 0.04 and p = 0.02, respectively).

Conclusions

CIN recurrence was associated with glandular involvement and compromised margins in cone biopsy and HIV infection. The presence of CpG islands hemimethylation in TIMP3 and MGMT genes is a promising triage method in CIN recurrence.

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References

  1. Vasiljević N, Scibior-Bentkowska D, Brentnall A, Cuzick J, Lorincz A (2014) A comparison of methylation levels in HPV18, HPV31 and HPV33 genomes reveals similar associations with cervical precancers. J Clin Virol 59(3):161–166

    Article  PubMed Central  PubMed  Google Scholar 

  2. Lima MI, Tafuri A, Araújo AC, de Miranda Lima L, Melo VH (2009) Cervical intraepithelial neoplasia recurrence after conization in HIV-positive and HIV-negative women. Int J Gynaecol Obstet 104(2):100–104

    Article  PubMed  Google Scholar 

  3. Lodi CT, Michelin MA, Lima MI, Teixeira NC, Adad SJ, Murta EF et al (2011) Factors associated with recurrence of cervical intraepithelial neoplasia after conization in HIV-infected and noninfected women. Arch Gynecol Obstet 284(1):191–197

    Article  PubMed  Google Scholar 

  4. Virmani AK, Muller C, Rathi A, Zoechbauer-Mueller S, Mathis M, Gazdar AF (2001) Aberrant methylation during cervical carcinogenesis. Clin Cancer Res 7(3):584–589

    CAS  PubMed  Google Scholar 

  5. Widschwendter A, Gattringer C, Ivarsson L, Fiegl H, Schneitter A, Ramoni A et al (2004) Analysis of aberrant DNA methylation and human papillomavirus DNA in cervicovaginal specimens to detect invasive cervical cancer and its precursors. Clin Cancer Res 10(10):3396–3400

    Article  CAS  PubMed  Google Scholar 

  6. Narayan G, Arias-Pulido H, Koul S, Vargas H, Zhang FF, Villella J et al (2003) Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome. Mol Cancer 2:24

    Article  PubMed Central  PubMed  Google Scholar 

  7. Luhn P, Walker J, Schiffman M, Zuna RE, Dunn ST, Gold MA et al (2013) The role of co-factors in the progression from human papillomavirus infection to cervical cancer. Gynecol Oncol 128(2):265–270

    Article  CAS  PubMed  Google Scholar 

  8. Bae JH, Kim CJ, Park TC, Namkoong SE, Park JS (2007) Persistence of human papillomavirus as a predictor for treatment failure after loop electrosurgical excision procedure. Int J Gynecol Cancer 17(6):1271–1277

    Article  CAS  PubMed  Google Scholar 

  9. Serati M, Siesto G, Carollo S, Formenti G, Riva C, Cromi A et al (2012) Risk factors for cervical intraepithelial neoplasia recurrence after conization: a 10-year study. Eur J Obstet Gynecol Reprod Biol 165(1):86–90

    Article  PubMed  Google Scholar 

  10. Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T et al (2013) Five-year risk of recurrence after treatment of CIN 2, CIN 3, or AIS: performance of HPV and Pap cotesting in posttreatment management. J Low Genit Tract Dis 17(5 0 1):S78–S84

    Article  PubMed Central  PubMed  Google Scholar 

  11. Russomano F, Paz BR, Camargo MJ, Grinstejn BG, Friedman RK, Tristao MA et al (2013) Recurrence of cervical intraepithelial neoplasia in human immunodeficiency virus-infected women treated by means of electrosurgical excision of the transformation zone (LLETZ) in Rio de Janeiro. Braz Sao Paulo Med J 131(6):405–410

    Google Scholar 

  12. Del Mistro A, Matteucci M, Insacco EA, Onnis G, Da Re F, Baboci L et al (2015) Long-term clinical outcome after treatment for high-grade cervical lesions: a retrospective monoinstitutional cohort study. Biomed Res Int 2015:984528

    PubMed  PubMed Central  Google Scholar 

  13. Herfs M, Somja J, Howitt BE, Suarez-Carmona M, Kustermans G, Hubert P et al (2015) Unique recurrence patterns of cervical intraepithelial neoplasia after excision of the squamocolumnar junction. Int J Cancer 136(5):1043–1052

    Article  CAS  PubMed  Google Scholar 

  14. Baloglu A, Uysal D, Bezircioglu I, Bicer M, Inci A (2010) Residual and recurrent disease rates following LEEP treatment in high-grade cervical intraepithelial lesions. Arch Gynecol Obstet 282(1):69–73

    Article  PubMed  Google Scholar 

  15. Cejtin HE, Malapati R, Chaparala S (2011) A comparison of loop electrosurgical excision procedures between human immunodeficiency virus-seropositive and -seronegative women. J Low Genit Tract Dis 15(1):37–41

    Article  PubMed  Google Scholar 

  16. Kodampur M, Kopeika J, Mehra G, Pepera T, Menon P (2013) Endocervical crypt involvement by high-grade cervical intraepithelial neoplasia after large loop excision of transformation zone: do we need a different follow-up strategy? J Obstet Gynaecol Res 39(1):280–286

    Article  PubMed  Google Scholar 

  17. Du R, Meng W, Chen ZF, Zhang Y, Chen SY, Ding Y (2013) Post-treatment human papillomavirus status and recurrence rates in patients treated with loop electrosurgical excision procedure conization for cervical intraepithelial neoplasia. Eur J Gynaecol Oncol 34(6):548–551

    CAS  PubMed  Google Scholar 

  18. Huchko MJ, Leslie H, Maloba M, Bukusi EA, Cohen CR (2014) Factors associated with recurrence of cervical intraepithelial neoplasia 2 + after treatment among HIV-infected women in Western Kenya. J Acquir Immune Defic Syndr 66(2):188–192

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Huchko MJ, Leslie H, Maloba M, Zakaras J, Bukusi E, Cohen CR (2015) Outcomes up to 12 Months after Treatment With Loop Electrosurgical Excision Procedure for Cervical Intraepithelial Neoplasia Among HIV-Infected Women. J Acquir Immune Defic Syndr 69(2):200–205

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Brentnall AR, Vasiljević N, Scibior-Bentkowska D, Cadman L, Austin J, Szarewski A et al (2014) A DNA methylation classifier of cervical precancer based on human papillomavirus and human genes. Int J Cancer 135(6):1425–1432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Lorincz AT (2014) Cancer diagnostic classifiers based on quantitative DNA methylation. Expert Rev Mol Diagn 14(3):293–305

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Vidal AC, Henry NM, Murphy SK, Oneko O, Nye M, Bartlett JA et al (2014) PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer. Clin Transl Oncol 16(3):266–272

    Article  CAS  PubMed  Google Scholar 

  23. Wentzensen N, Sherman ME, Schiffman M, Wang SS (2009) Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science. Gynecol Oncol 112(2):293–299

    Article  CAS  PubMed  Google Scholar 

  24. Szalmás A, Kónya J (2009) Epigenetic alterations in cervical carcinogenesis. Semin Cancer Biol 19(3):144–152

    Article  PubMed  Google Scholar 

  25. De Vuyst H, Franceschi S, Plummer M, Mugo NR, Sakr SR, Meijer CJ et al (2015) Methylation levels of CADM1, MAL, and MIR124-2 in cervical scrapes for triage of HIV-infected, high-risk HPV-positive women in Kenya. J Acquir Immune Defic Syndr 70(3):311–318

    Article  PubMed  Google Scholar 

  26. Walker P, Dexeus S, de Palo G, Barrasso R, Campion M, Girardi F et al. (2009) International terminology of colposcopy: an updated report from the international federation for cervical pathology and colposcopy. Available http://www.ifcpc.org/ifcpc/terminology. Accessed 12 Sept 2009

  27. Smith JH (2002) Bethesda 2001. Cytopathology 13(1):4–10

    Article  CAS  PubMed  Google Scholar 

  28. Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93(18):9821–9826

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Heard I, Potard V, Foulot H, Chapron C, Costagliola D, Kazatchkine MD (2005) High rate of recurrence of cervical intraepithelial neoplasia after surgery in HIV-positive women. J Acquir Immune Defic Syndr 39(4):412–418

    Article  PubMed  Google Scholar 

  30. Nappi L, Carriero C, Bettocchi S, Herrero J, Vimercati A, Putignano G (2005) Cervical squamous intraepithelial lesions of low-grade in HIV-infected women: recurrence, persistence, and progression, in treated and untreated women. Eur J Obstet Gynecol Reprod Biol 121(2):226–232

    Article  CAS  PubMed  Google Scholar 

  31. Malapati R, Chaparala S, Cejtin HE (2011) Factors influencing persistence or recurrence of cervical intraepithelial neoplasia after loop electrosurgical excision procedure. J Low Genit Tract Dis 15(3):177–179

    Article  PubMed  Google Scholar 

  32. Terra AP, Murta EF, Maluf PJ, Caballero OL, Brait M, Adad SJ (2007) Aberrant promoter methylation can be useful as a marker of recurrent disease in patients with cervical intraepithelial neoplasia grade III. Tumori 93(6):572–579

    Article  CAS  PubMed  Google Scholar 

  33. Kong TW, Son JH, Chang SJ, Paek J, Lee Y, Ryu HS (2014) Value of endocervical margin and high-risk human papillomavirus status after conization for high-grade cervical intraepithelial neoplasia, adenocarcinoma in situ, and microinvasive carcinoma of the uterine cervix. Gynecol Oncol 135(3):468–473

    Article  PubMed  Google Scholar 

  34. Ryu A, Nam K, Kwak J, Kim J, Jeon S (2012) Early human papillomavirus testing predicts residual/recurrent disease after LEEP. J Gynecol Oncol 23(4):217–225

    Article  PubMed Central  PubMed  Google Scholar 

  35. Fu Y, Chen C, Feng S, Cheng X, Wang X, Xie X et al (2015) Residual disease and risk factors in patients with high-grade cervical intraepithelial neoplasia and positive margins after initial conization. Ther Clin Risk Manag 11:851–856

    Article  PubMed Central  PubMed  Google Scholar 

  36. Manchanda R, Baldwin P, Crawford R, Vowler SL, Moseley R, Latimer J et al (2008) Effect of margin status on cervical intraepithelial neoplasia recurrence following LLETZ in women over 50 years. BJOG 115(10):1238–1242

    Article  CAS  PubMed  Google Scholar 

  37. Jin J, Li L, Zhang F (2015) Meta-analysis of high risk factors of residue or relapse of cervical intraepithelial neoplasia after conization. J Biol Regul Homeost Agents 29(2):451–458

    CAS  PubMed  Google Scholar 

  38. van Bogaert LJ (2015) Involved LEEP excision margins as predictor of residual/recurrent disease in HIV-positive and HIV-negative women in a low-resource setting. Anal Quant Cytopathol Histpathol 37(2):105–108

    PubMed  Google Scholar 

  39. Wu J, Jia Y, Luo M, Duan Z (2016) Analysis of residual/recurrent disease and its risk factors after loop electrosurgical excision procedure for high-grade cervical intraepithelial neoplasia. Gynecol Obstet Invest 81(4):296–301

    Article  CAS  PubMed  Google Scholar 

  40. Thomison J, Thomas LK, Shroyer KR (2008) Human papillomavirus: molecular and cytologic/histologic aspects related to cervical intraepithelial neoplasia and carcinoma. Hum Pathol 39(2):154–166

    Article  CAS  PubMed  Google Scholar 

  41. Petrova YI, Schecterson L, Gumbiner BM (2016) Roles for E-cadherin cell surface regulation in cancer. Mol Biol Cell 27(21):3233–3244

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Banzai C, Nishino K, Quan J, Yoshihara K, Sekine M, Yahata T et al (2014) Promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A genes in cervical carcinoma. Int J Clin Oncol 19(1):127–132

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank FAPEMIG for the financial support in this study.

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Authors and Affiliations

Authors

Contributions

CTCL: Project development, data collection, data analysis, manuscript writing.MAM: Project development. MIML: Data collection. EFCM: Project development. LCB: data analysis, manuscript writing. LM: Project development.

VHM-Project development, Data Collection, Data analysis, Manuscript writing.

Corresponding author

Correspondence to Claudia Teixeira da Costa Lodi.

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The authors declare that they have no conflicts of interest.

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All procedures performed in studies in volving human participants were in accordance with the ethical standards of the institutional and/or national research committee and withthe 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Teixeira da Costa Lodi, C., Michelin, M.A., Miranda Lima, M.I. et al. Predicting cervical intraepithelial neoplasia recurrence in HIV-infected and -noninfected women by detecting aberrant promoter methylation in the CDH1, TIMP3, and MGMT genes. Arch Gynecol Obstet 298, 971–979 (2018). https://doi.org/10.1007/s00404-018-4899-x

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  • DOI: https://doi.org/10.1007/s00404-018-4899-x

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