Role of FAM19A4/miR124-2 methylation analysis in predicting regression or non-regression of CIN2/3 lesions: A protocol of an observational longitudinal cohort study: a protocol of an observational longitudinal cohort study

Wieke W. Kremer, Johannes Berkhof, Maaike C. G. Bleeker, Daniëlle A. M. Heideman, Nienke E. van Trommel, Marchien W. van Baal, Harold R. Verhoeve, Chris J. L. M. Meijer, Gemma G. Kenter

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Introduction: The clinical course of high-grade cervical intraepithelial neoplasia (CIN2/3) is characterised by a high spontaneous regression rate. Histological assessment is unable to differentiate between CIN2/3 lesions likely to regress and those likely to persist or progress. Most CIN2/3 lesions are treated by surgical excision, leading to overtreatment of a substantial proportion. In this prospective study, we evaluate the value of DNA methylation of host cell genes, which has shown to be particularly sensitive for the detection of advanced CIN2/3 and cervical cancer, in the prediction of regression or non-regression of CIN2/3 lesions. Methods and analysis: This is a multicentre observational longitudinal study with 24-month follow-up. Women referred for colposcopy with an abnormal cervical scrape, who have been diagnosed with CIN2/3 and a small cervical lesion (≤50% of cervix) will be asked to participate. Participants will be monitored by 6-monthly cytological and colposcopic examination. In case of clinical progression, participants will receive treatment and exit the study protocol. At baseline and during follow-up, self-sampled cervicovaginal brushes and cervical scrapes will be collected for high-risk human papillomavirus (HPV) testing and FAM19A4/miR124-2 methylation analysis. A colposcopy-directed biopsy will be taken from all participants at the last follow-up visit. The primary study endpoint is regression or non-regression at the end of the study based on the histological diagnosis. Regression is defined as CIN1 or less. Non-regression is defined as CIN2 or worse. The secondary study endpoint is defined as HPV clearance (double-negative HPV test at two consecutive time-points). The association between methylation status and regression probability will be evaluated by means of χ2 testing. Ethics and dissemination: Ethics approval was obtained in all participating clinics. Results: of the main study will be submitted for publication in a peer-reviewed journal.
Original languageEnglish
Article numbere029017
Pages (from-to)e029017
JournalBMJ Open
Issue number7
Publication statusPublished - 1 Jul 2019


  • DNA methylation
  • cervical intraepithelial neoplasia
  • colposcopy
  • human papillomavirus
  • natural history
  • overtreatment

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