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. 2025 Jul 14.
doi: 10.1111/1471-0528.18288. Online ahead of print.

DNA-Methylation for Risk-Stratification of Women Without a Fully Visible Transformation Zone at Colposcopy: A Cross-Sectional Study

Karen Omann Binderup  1   2 , Joachim Boers  3   4 , Line Winther Gustafson  1   5 , Berit Andersen  1   6 , Lone Kjeld Petersen  7   8 , Pinar Bor  5   6 , Joost Gribnau  3   4 , Wim G V Quint  4 , Henk Van Den Munckhof  4 , Mette Tranberg  1   6 , Anne Hammer  2   6
Affiliations

DNA-Methylation for Risk-Stratification of Women Without a Fully Visible Transformation Zone at Colposcopy: A Cross-Sectional Study

Karen Omann Binderup et al. BJOG. .

Abstract

Objective: To evaluate the performance of DNA methylation markers for the detection of cervical precancer among screening-positive older women without a fully visible transformation zone at colposcopy (TZ3).

Design: Cross-sectional study.

Setting: Colposcopy clinics, Central Denmark Region, 2019-2021.

Population: Women ≥ 45 years with a TZ3 at colposcopy.

Methods: Participants referred for colposcopy due to an abnormal cervical screening test underwent cervical cytology sampling, biopsies and a large loop excision of the transformation zone (LLETZ). Cytology samples were analysed for DNA methylation markers: FAM19A4/miR124-2, ARID3C/ARL5C and METloc001/METloc002 according to the manufacturer's instructions. LLETZ histology was the reference standard.

Main outcome measures: Sensitivity and specificity of the methylation markers for cervical intraepithelial grade 2 or worse (CIN2+) and cervical intraepithelial grade 3 or worse (CIN3+).

Results: Among 89 women (median age: 67.9 years), 31 (34.8%) had CIN2+ and 16 (18.0%) had CIN3+ detected. Sensitivity for CIN2+ was similar across markers, ranging from 74.2% (95% CI: 55.4-88.1) to 77.4% (95% CI: 58.9-90.4), while specificity was lower for FAM19A4/miR124-2 (39.7%; 95% CI: 27.0-53.4) compared to ARID3C/ARL5C (65.5%; 95% CI: 51.9-77.5) and METloc001/METloc002 (82.8%; 95% CI: 70.6-91.4). Sensitivity for CIN3+ was slightly lower for FAM19A4/miR124-2 (75.0%; 95% CI: 47.6-92.7) compared to ARID3C/ARL3C (87.5%; 95% CI: 61.7-98.4) and METloc001/METloc002 (93.8%; 95% CI: 69.8-99.8). Similarly, specificity was lowest for FAM19A4/miR124-2 (35.6%; 95% CI: 24.7-47.7), higher for ARID3C/ARL5C (60.3%; 95% CI: 48.1-71.5) and highest for METloc001/METloc002 (93.8%; 95% CI: 63.9-84.7).

Conclusions: Methylation markers, particularly METloc001/METloc002, may be useful for risk-based management of women with a TZ3 at colposcopy.

Trial registration: ClinicalTrials.gov identifier: NCT04298957 (https://www.

Clinicaltrials: gov/ct2/show/NCT04298957?term=NCT04298957&draw=2&rank=1).

Keywords: DNA‐methylation; LLETZ; cervical intraepithelial neoplasia; diagnostics; transformation zone type 3.

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References

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    1. N. Wentzensen, J. L. Walker, M. A. Gold, et al., “Multiple Biopsies and Detection of Cervical Cancer Precursors at Colposcopy,” Journal of Clinical Oncology 33, no. 1 (2015): 83–89.
    1. L. W. Gustafson, L. K. Petersen, P. Bor, B. Andersen, and A. Hammer, “Cervical Cancer Prevention Among Older Women – Challenges in Screening, Diagnostic Workup and Treatment,” Acta Obstetricia et Gynecologica Scandinavica 100, no. 8 (2021): 1364–1368.
    1. L. W. Gustafson, A. Hammer, M. H. Bennetsen, et al., “Cervical Intraepithelial Neoplasia in Women With Transformation Zone Type 3: Cervical Biopsy Versus Large Loop Excision,” BJOG: An International Journal of Obstetrics & Gynaecology 129 (2022): 2132–2140, https://doi.org/10.1111/1471‐0528.17200.
    1. W. Prendiville and R. Sankaranarayanan, Colposcopy and Treatment of Cervical Precancer (IARC Technical Publications, 2017).

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