Clinical Performance of Methylation as a Biomarker for Cervical Carcinoma In Situ and Cancer Diagnosis: A Worldwide Study

Authors

Cristiana Banila, Centre for Cancer Prevention, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
Attila T. Lorincz, Centre for Cancer Prevention, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
Dorota Scibior-Bentkowska, Centre for Cancer Prevention, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
Gary M. Clifford, 2 Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
Birhanu Kumbi, Department of Microbial, Cellular and Molecular Biology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa, Ethiopi
Dereje Beyene, Department of Microbial, Cellular and Molecular Biology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa, Ethiopi
Cosette M. Wheeler, Centre for HPV Prevention, University of New Mexico Comprehensive Cancer Centre, Albuquerque, New Mexico, USA
Kate Cuschieri, Scottish HPV Reference Laboratory, Department of Laboratory Medicine, University of Edinburgh, Edinburgh, UK
Jack Cuzick, Centre for Cancer Prevention, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
Belinda Nedjai, Centre for Cancer Prevention, Wolfson Institute of Population Health, Queen Mary University of London, London, UK

Document Type

Article

Publication Date

1-15-2022

Abstract

The shift towards primary human papillomavirus (HPV)-based screening has necessitated the search for a secondary triage test that provides sufficient sensitivity to detect high-grade cervical intraepithelial neoplasia (CIN) and cancer, but also brings an improved specificity to avoid unnecessary clinical work and colposcopy referrals. We evaluated the performance of the previously described DNA-methylation test (S5) in detecting CIN3 and cancers from diverse geographic settings in high-, medium- and low-income countries, using the cut-off of 0.80 and exploratory cut-offs of 2.62 and 3.70. Assays were performed using exfoliated cervical specimens (n = 808) and formalin-fixed biopsies (n = 166) from women diagnosed with cytology-negative results (n = 220), CIN3 (n = 204) and cancer stages I (n = 245), II (n = 249), III (n = 28) and IV (n = 22). Methylation increased proportionally with disease severity (Cuzick test for trend, P < .0001). S5 accurately separated women with negative-histology from CIN3 or cancer (P < .0001). At the 0.80 cut-off, 543/544 cancers were correctly identified as S5 positive (99.81%). At cut-off 3.70, S5 showed a sensitivity of 95.77% with improved specificity. The S5 odds ratios of women negative for cervical disease vs CIN3+ were significantly higher than for HPV16/18 genotyping at all cut-offs (all P < .0001). At S5 cut-off 0.80, 96.15% of consistently high-risk human papillomavirus (hrHPV)-negative cancers (tested with multiple hrHPV-genotyping assay) were positive by S5. These cancers may have been missed in current primary hrHPV-screening programmes. The S5 test can accurately detect CIN3 and malignancy irrespective of geographic context and setting. The test can be used as a screening and triage tool. Adjustment of the S5 cut-off can be performed considering the relative importance given to sensitivity vs specificity.

Recommended Citation

Banila C, Lorincz AT, Scibior-Bentkowska D, Clifford GM, Kumbi B, Beyene D, Wheeler CM, Cuschieri K, Cuzick J, Nedjai B. Clinical performance of methylation as a biomarker for cervical carcinoma in situ and cancer diagnosis: A worldwide study. Int J Cancer. 2022 Jan 15;150(2):290-302. doi: 10.1002/ijc.33815. Epub 2021 Oct 11. PMID: 34562270; PMCID: PMC8627461.