Journal Article

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer

Barrett, James E., Widschwendter, Martin, Sundström, Karin, Dillner, Joakim, Evans, Iona, Jones, Allison, Wang, Jiangrong, Herzog, Chiara

2022

Overview

Background Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. Methods We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1–4 years and 218 remained disease-free. Results We developed the WID-CIN (Women’s cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88–0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3–96.1) in all and 92.7% (85.9–99.6) and 65.6% (49.2–82.1) in women aged ≥30 and <30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0–61.5) cases developing 1–4 years after sample donation in all ages or 56.9% (47.6–66.2) and 53.5% (43.7–63.2) in ≥30 and <30-year-old women, at a specificity of 75%. Conclusions The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Age groups / Biobanks / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cellular biology / Cervical cancer / Cervical cancer screening / Cervix / Cervix dysplasia / Colposcopy / CpG islands / Cytology / Diagnosis / Diagnostics / DNA methylation / Early Detection of Cancer - methods / Female / Genomes / Genomics / Human Genetics / Human papillomavirus / Humans / Invasiveness / Laboratories / Liquid-based cytology / Medical screening / Medicine/Public Health / Metabolomics / Methylation / Papillomaviridae - genetics / Papillomavirus infections / Papillomavirus Infections - diagnosis / Personal identification numbers / Pregnancy / Sensitivity analysis / Systems Biology / Uterine Cervical Dysplasia - diagnosis / Uterine Cervical Dysplasia - genetics / Uterine Cervical Dysplasia - pathology / Uterine Cervical Neoplasms - diagnosis / Uterine Cervical Neoplasms - pathology / Women / Womens health