Abstract
Several studies have demonstrated that the viral genome can be methylated by the host cell during progression from persistent infection to cervical cancer. The aim of this study was to investigate whether methylation at a specific site could predict the development of viral persistence and whether viral load shows a correlation with specific methylation patterns. HPV16‐positive samples from women aged 20–29 years (n = 99) with a follow‐up time of 13 years, were included from a Danish cohort comprising 11 088 women. Viral load was measured by real‐time PCR and methylation status was determined for 39 CpG sites in the upstream regulatory region (URR), E6/E7, and L1 region of HPV16 by next‐generation sequencing. Participants were divided into two groups according to whether they were persistently (≥ 24 months) or transiently HPV16 infected. The general methylation status was significantly different between women with a persistent and women with a transient infection outcome (P = .025). One site located in L1 (nt. 5962) was statistically significantly (P = .00048) different in the methylation status after correction using the Holm‐Sidak method (alpha = 0.05). Correlation analyses of samples from HPV16 persistently infected women suggest that methylation is higher although viral load is lower. This study indicates that methylation at position 5962 of the HPV16 genome within the L1 gene might be a predictive marker for the development of a persistent HPV16 infection.
Highlights
A persistent infection with high risk (HR) types of human papillomaviruses (HPV) is a necessary precondition for cervical cancer.[1]
In this prospective cohort study, we investigated viral DNA methylation of HPV16 at 39 CpG sites in the upstream regulatory region (URR), E6/E7, and L1 region
Our observations show that it might be possible to predict a persistent infection as a risk factor for disease progression after a single test at a given time point
Summary
A persistent infection with high risk (HR) types of human papillomaviruses (HPV) is a necessary precondition for cervical cancer.[1]. While the vast majority of women acquire a HR HPV infection during their lifetime, only a minority of infections persist and progress to cervical cancer or precancerous lesions, defined as high-grade cervical intraepithelial neoplasia grade 3 (CIN3+).[2] In a time span of 2-3 decades, approximately a third of untreated CIN3 lesions become invasive and progress to cervical cancer.[3] The transition from a productive to a transforming infection from CIN1 to CIN3 lesions is characterized by a substantial change in HPV gene expression, from high-level structural gene (L1 and L2) expression and low oncogene (E6 and E7) expression to high expression of oncogenes that interfere with cellular apoptosis and cell cycle regulation and diminished expression of structural proteins.[4] Altered viral gene expression has been linked to methylation of the viral genome for several DNA viruses including Kaposi Sarcoma Herpesvirus, Epstein-Barr Virus, Simian Virus 40 and Adenoviruses (reviewed by 5). It has been demonstrated that the papillomavirus genome is de novo methylated by DNMTs of the host cell that play a role in innate immunity.[5,7] methylation of the viral genome might be a novel mechanism by which the host cell regulates viral gene expression and thereby HPV pathogenicity
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