2016
Epigenetic markers on the horizon: how to triage hrHPV positive women

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Ongoing cohort study, cross-section analysis of more than 2,000 Hungarian women

Adrienn Kocsis1, Marta Benczik1,4, Robert Koiss2, Zsuzsa Schaff3, Miklos Nyiri1, Tibor Takacs1,4

1) Cellcall Kft., Budapest, Hungary

2) Department of Obstetrics and Gynaecology, St. Stephan’s Hospital, Budapest, Hungary

3) Second Department of Pathology, Semmelweis University, Budapest, Hungary

4) GenoID Molecular Diagnostic Laboratory, Synlab Hungary Kft., Budapest, Hungary

KEYWORDS: HPV, cervical screening, cytology, biomarkers, gene methylation, epigenetics

OBJECTIVES. The most recent guidelines recommend primary high-risk HPV (HR-HPV) screening as an alternative to cytology-based cervical cancer screening. Although HR-HPV detection has high sensitivity, it is not specific enough, leading to a substantial false positive rate. In our ongoing multicentric clinical study we investigated an epigenetic molecular biomarker, based on host gene methylation, as a potential triage method of HR-HPV positive women.

METHODS. Over 2,000 cervical specimens were obtained for liquid-based cytology and high-risk HPV tests (Cellcall Confidence HPV and Roche™ Cobas®4800 HPV), from women aged 25 years or older, presenting for cervical screening. Host DNA methylation test (Cellcall Confidence Marker) was carried out on bisulphite converted DNA. In clinically indicated cases, diagnostic histology was used as a ’gold standard’ reference method. In the absence of histologically confirmed diagnosis, negative histology result was presumed.

RESULTS. 24.5% of the samples was HR-HPV positive, 9.1% was methylation positive. Primary HR-HPV test followed by gene methylation triage was 96.7% (95% CI: 95.8-97.5) specific for high grade lesions (CIN3+), the negative predictive value was 99.7% (95% CI: 92.3-99.9). The triage test had a sensitivity of 88.2% (95% CI: 72.6-96.7), a specificity of 85.8% (95% CI: 82.0-89.0) and positive predictive value of 33.3% (95% CI: 23.7-44.1) for CIN3+ in HR-HPV positive cases.

CONCLUSION. We recommend sensitive primary HPV screening followed by a triage of positive cases using highly specific molecular biomarkers. Epigenetic approach has potential clinical utility in the management of HR-HPV positive women.

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