Predicting cervical intraepithelial neoplasia recurrence in HIV-infected and -noninfected women by detecting aberrant promoter methylation in the CDH1, TIMP3, and MGMT genes
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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.
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.
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).
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.
KeywordsDNA methylation Human immunodeficiency virus Cervical intraepithelial neoplasia Recurrence Loop electrosurgical excision procedure Human papillomavirus
We thank FAPEMIG for the financial support in this study.
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
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.
Informed consent was obtained from all individual participants included in the study.
- 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):3396–3400CrossRefPubMedCentralGoogle 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):405–410Google 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):280–286CrossRefPubMedCentralGoogle 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):548–551PubMedPubMedCentralGoogle 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
- 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):226–232CrossRefPubMedCentralGoogle 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):468–473CrossRefPubMedCentralGoogle Scholar