Methylation in predicting progression of untreated high-grade cervical intraepithelial neoplasia
Clinical Infectious Diseases
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Background There is no baseline prognostic test to ascertain whether cervical intraepithelial neoplasia (CIN) will regress or progress. The majority of CIN regress in young women and since local treatments are known to increase the risk of adverse pregnancy outcomes interventions need to be sparing. We investigated the ability of a DNA methylation panel (the S5-classifier) to discriminate between progression and regression among women of childbearing age with untreated CIN grade 2 (CIN2). Methods Pyrosequencing methylation and HPV genotyping assays were performed on exfoliated cervical cells from 149 young women with CIN2 in a 2-year cohort study of active surveillance. Results Twenty-five lesions progressed to CIN grade 3 or worse, 88 regressed to less than CIN grade 1, and 36 lesions persisted as CIN1/2. When cytology, HPV16/18- and HPV16/18/31/33-genotyping, and S5 at baseline were compared to outcomes, S5 was the strongest biomarker associated with regression versus progression. S5 alone or in combination with HPV16/18/31/33-genotyping also showed significantly increased sensitivity versus cytology, comparing regression vs. persistence/progression. With both S5 and cytology tests set at a specificity of 38.6% (95% CI 28.4-49.6) the sensitivity of S5 was significantly higher (83.6%, 95% CI 71.9-91.8) than for cytology (62.3%, 95% CI 49.0-74.4) (p=0.005). The highest area under the curve (AUC) was 0.735 (95% CI 0.621-0.849) in the regression vs. progression outcome with a combination of S5 and cytology, whereas HPV16/18 or HPV16/18/31/33-genotyping did not provide additional prognostic information. Conclusions The S5-classifier shows high potential as a prognostic biomarker to identify women with progressive CIN2.