The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review

Abstract

This paper briefly reviews the role of hypermethylation of host cell genes in cervical carcinogenesis and discusses potential clinical applications of methylation analysis in the management of highrisk HPV (hrHPV) -positive women. We argue that methylation assays can be used: 1. for primary triage of hrHPV-positive women to detect cervical cancer and advanced cervical intraepithelial neoplasia (CIN); 2. as secondary triage for women with minor cytological abnormalities to identify those with the highest risk of CIN3 or worse; 3. as exit test for women leaving the screening programme to identify cervical cancer and advanced CIN; and 4. to support management of CIN.

Re: Reflex cytology for triage of high‐risk human papillomavirus positive self‐sampled material in cervical cancer screening: a prospective cohort study

“…Major benefits of methylation such as high reproducibility, sensitivity and specificity have been confirmed by growing evidence. 3 In summary, the study by Loopik et al was useful in focusing on CS for the triage of hrHPV-positive CS, and reinforcing the need to reduce diagnostic delay and loss to follow-up. 1 Challenges remain because of the low sensitivity for detecting CIN2+ and the limitation of descriptive studies lacking accuracy comparisons with clinically common strategies.…”

“…Clinically, pregnant women with the more severe COVID-19 infection appear to prefer delivery by caesarean delivery rather than vaginal birth. [2][3][4] Therefore, it is possible that any beneficial effects of caesarean birth in reducing transmission of COVID-19 might not be apparent because the severity of COVID-19 infection was greater in these women. This selective bias would weaken the conclusions of current studies.…”

“…Cytology triage on CS is limited by low sensitivity and the need for substantial repeat testing. 3 The main site of hrHPV infection is at the transformation zone of the cervix, but self samples contain a mixture of vaginal and exfoliated cervical cells, 2 often lacking endocervical cells and thereby lowering the sensitivity of the test. Likewise, as a result of low sensitivity (confirmed in a pilot study), cytology-based tests such as p16/ki-67 or p16 cytology staining on CS cannot currently be advocated as part of cervical screening programmes.…”

“…We thank Song et al for their insightful comments 1 on our article 2 and commend them for their study about human papillomavirus (HPV)-genotyping on self-samples and their analysis on different triage strategies for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+). 3 They report that cytology on physician-sampled material has a sensitivity of 74.8% for detecting CIN2+, whereas HPV-genotyping for types 16/18 has a sensitivity of 52.6% for detecting CIN2+. This means that HPV-genotyping in their hands is still inferior to cytology testing and cannot fully replace this triage strategy.…”

Association between PEG3 DNA methylation and high-grade cervical intraepithelial neoplasia

“…DNA methylation in genes and HPV testing have been investigated as triage methods to improve risk stratification of HR-HPV positive women. Studies summarizing the performance of DNA methylation in CIN2 and CIN3 detection have reported significantly higher DNA methylation in CIN2+ and CIN3+ compared to ≤ CIN1 [ 10 , 14 ]. We previously reported that aberrant methylation at DMRs that regulate the expression of imprinted genes including Insulin-like Growth Factor 2 (which expresses IGF2, a potent mitogen), Paternally Expressed Gene 1/Mesoderm-Specific Transcript ( PEG1/MEST ) and Paternally Expressed Gene 3 ( PEG3 ) were independent predictors of CIN2/3 and ICC in a cross-sectional study of Tanzanian women with CIN and ICC [ 15 , 16 ].…”