The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer
| dc.contributor.author | Barrett, James E. | |
| dc.contributor.author | Sundström, Karin | |
| dc.contributor.author | Jones, Allison | |
| dc.contributor.author | Evans, Iona | |
| dc.contributor.author | Wang, Jiangrong | |
| dc.contributor.author | Herzog, Chiara | |
| dc.contributor.author | Dillner, Joakim | |
| dc.contributor.author | Widschwendter, Martin | |
| dc.date.accessioned | 2023-02-27T18:32:23Z | |
| dc.date.available | 2023-02-27T18:32:23Z | |
| dc.date.issued | 2022-10-19 | |
| dc.description.abstract | 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. | en_US |
| dc.identifier.citation | Barrett, J. E., Sundström, K., Jones, A., Evans, I., Wang, J., Herzog, C., Dillner, J., & Widschwendter, M. (2022). The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer. Genome medicine, 14(1), 116. https://doi.org/10.1186/s13073-022-01116-9 | en_US |
| dc.identifier.other | DOI: 10.1186/s13073-022-01116-9 | |
| dc.identifier.uri | https://hdl.handle.net/20.500.14041/5872 | |
| dc.language.iso | en_US | en_US |
| dc.publisher | Genome medicine | en_US |
| dc.rights | Attribution-NonCommercial-NoDerivs 3.0 United States | * |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/us/ | * |
| dc.subject | DNA Methylation | en_US |
| dc.subject | Cervical Cancer Screening | en_US |
| dc.subject | Diagnostics | en_US |
| dc.subject | Liquid-Based Cytology | en_US |
| dc.title | The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer | en_US |
| dc.type | Article | en_US |