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Abstract
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.
Trial registration number NTR6069; Pre-results
- cervical intraepithelial neoplasia
- colposcopy
- human papillomavirus
- DNA methylation
- overtreatment
- natural history
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Footnotes
Contributors WWK, JB, MCGB, DAMH, NEvT, CJLMM and GGK were involved in conception and study design. WWK, CJLMM and GGK were involved in drafting of the article. JB, MCGB, DAMH, NEvT, MWB and HRV were involved in critical revision of the article for important intellectual content. All authors critically reviewed the manuscript and approved the final version. JB provided statistical expertise. WWK, MWB and HRV will be involved in data acquisition. Collection, management, analysis and interpretation of data, writing of the report, and the decision to submit the report for publication is the responsibility of GGK, the principal investigator of the study.
Funding This work was supported by ZonMw grant number 531002010.
Competing interests DAMH and CJLMM are minority shareholders of Self-screen B.V., a spin-off company of VU University Medical Center; Self-screen B.V. holds patents related to the work (ie, high-risk HPV test and methylation markers for cervical screening); DAMH has been on the speakers bureau of Qiagen and serves occasionally on the scientific advisory boards of Pfizer and Bristol-Myers Squibb; JB received consultancy fees from Roche, GlaxoSmithKline and Merck, and received travel support from DDL. All fees were collected by his employer; CJLMM has received speakers fee from GSK, Qiagen, and SPMSD/Merck, and served occasionally on the scientific advisory board (expert meeting) of GSK, Qiagen, and SPMSD/Merck; CJLMM has a very small number of shares of Qiagen and holds minority stock in Self-screen B.V.; CJLMM is part-time director of Self-screen B.V. since September 2017.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.