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Human Papillomavirus DNA methylation as a biomarker for cervical precancer: Consistency across 12 genotypes and potential impact on management of HPV-positive women

Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV-positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated. In this nested case-control study, we tested up to 30 cases of precancer (CIN3/AIS) and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, odds ratios, and areas under the curve (AUC). Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies. Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden’s index (0.46), compared with cytology (0.31) and a 5-type methylation assay including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared to cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology- or HPV16/18-positives. HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multi-type methylation assay may serve as a triage test for HPV-positive women.

Authors: Clarke MA; Gradíssimo A; Schiffman M; Lam J; Sollecito CC; Fetterman B; Lorey T; Poitras NE; Raine-Bennett T; Castle PE; Wentzensen N; Burk RD

Clin Cancer Res. 2018 Feb 02.

PubMed abstract

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