Integrated virus-host methylome analysis in head and neck squamous cell carcinoma

Abstract

One in six cancers worldwide is caused by infection and human papillomavirus (HPV) is one of the main culprits. To better understand the dynamics of HPV integration and its effect on both the viral and host methylomes, we conducted whole-genome DNA methylation analysis using MeDIP-seq of HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC). We determined the viral subtype to be HPV-16 in all cases and show that HPV-16 integrates into the host genome at multiple random sites and that this process predominantly involves the transcriptional repressor gene (E2) in the viral genome. Comparative analysis identified 453 (FDR ≤ 0.01) differentially methylated regions (DMRs) in the HPV+ host methylome. Bioinformatics characterization of these DMRs confirmed the previously reported cadherin genes to be affected but also revealed new targets for HPV-mediated methylation changes at regions not covered by array-based platforms, including the recently identified super-enhancers.

Keywords: :

• human papillomavirus (HPV)
• head and neck squamous cell carcinoma (HNSCC)
• DNA methylation
• methylome
• epigenome

Disclosure of Potential Conflicts of Interests

No potential conflicts of interest were disclosed.

Note

MeDIP-Seq data were submitted to GEO (Gene Expression Omnibus, NCBI) according to the instructions provided (GEO accession number: GSE38263).

Acknowledgments

We would like to thank Dr Susanne Gollin and Dr. Theresa Whiteside (University of Pittsburgh Cancer Institute, US), Dr Hans Joenje (VU Medical Center, Netherlands) and Dr Thomas Carey (University of Michigan, US) for the provision of HNSCC cell lines. We would also like to thank the teams at the Head and Neck Centre and the Department of Histopathology at the University College London Hospital (UCLH), UCL Advanced Diagnostics and UCL Genomics for their support. This study was supported in part by the UCLH Comprehensive Biomedical Research Centre (CBRC). The UCLH Head and Neck Tumour Bank was supported by UCLH/UCL NIHR CBRC. HC was supported by the Swedish Research Council and the Wenner-Gren foundation. ML was supported by a Wellcome Trust Fellowship (WT093855MA) and the Austrian Science Fund (J2856). AK was supported by a Cancer Research UK PhD Fellowship. Research in the Boshoff lab was supported by Cancer Research UK. Research in the Beck lab was supported by the Wellcome Trust (084071), Royal Society Wolfson Research Merit Award (WM100023) and IMI-JU OncoTrack (115234).

Supplemental Materials

Supplemental materials may be found here: www.landesbioscience.com/journals/epigenetics/article/25614