Introduction/Background Cervical cancer is the fourth most common malignancy in women worldwide. Current cervical screening programmes use a primary screening test of high-risk HPV (hr-HPV) testing or cytology to identify at risk women. hrHPV testing has a high sensitivity but low specificity for high-grade CIN and Cancer. As a result, DNA methylation testing has been suggested as a triage test for hrHPV positive women. As yet, there is no consensus on the most accurate methylation markers for use in screening. We conducted a systematic review and meta-analysis to determine the diagnostic test accuracy of human and HPV DNA methylation markers.
Methodology MEDLINE, EMBASE, and ongoing trial registries were systematically searched from inception to February 2023. DNA methylation diagnostic test accuracy studies using histopathology as a reference standard were included. Sensitivity and specificity data were extracted: a bivariate random-effects model was applied to calculate pooled estimates and corresponding heterogeneity, which was explored in a series of sensitivity analyses.
Results Twenty-eight studies including 6,956 women were meta-analysed, producing pooled estimates for genes C13ORF18, EPB41L3, FAM19A4, HPV16:L1, JAM3, PAX1, SOX1, and ZNF582. PAX1 was the most accurate marker of CIN2+ with a pooled area under the curve (AUC) of 0.93 (95% confidence interval (CI) 0.90–0.95) and pooled AUC of 0.87 (95%CI 0.84–0.90) for CIN3+. HPV16:L1 was the second-best marker of CIN2+; pooled AUC 0.83 (95%CI 0.80–0.86). JAM3 was the most accurate marker of CIN3+; pooled AUC 0.88 (95%CI 0.85–0.91).
Conclusion PAX1 methylation testing appears to be the most accurate methylation marker for high-risk CIN and Cancer. Specificity may surpass cytology allowing the potential to triage patients more effectively to colposcopy or conservative management. Our analysis has also elucidated several other genes which show promise for use in methylation marker panels, combined panels may provide greater accuracy than stand-alone methylation markers.
Disclosures No disclosures
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