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Identification and functional validation of HPV-mediated hypermethylation in head and neck squamous cell carcinoma.

Lechner, M; Fenton, T; West, J; Wilson, G; Feber, A; Henderson, S; Thirlwell, C; ... Beck, S; + view all (2013) Identification and functional validation of HPV-mediated hypermethylation in head and neck squamous cell carcinoma. Genome Medicine , 5 (2) p. 15. 10.1186/gm419. Green open access

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Abstract

ABSTRACT: BACKGROUND: Human Papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) represents a distinct clinical and epidemiological entity compared with HPV negative (HPV-) HNSCC. To test the possible involvement of epigenetic modulation by HPV in HNSCC, we conducted a genome-wide DNA methylation analysis. METHODS: Using laser-capture microdissection of 42 formalin-fixed paraffin-embedded (FFPE) HNSCCs, we generated DNA methylation profiles of 18 HPV+ and 14 HPV- samples, using the Infinium 450k BeadArray technology. Methylation data were validated in two sets of independent HPV+/HPV- HNSCC samples (fresh frozen and cell lines) using two independent methods (Infinium 450k and whole-genome MeDIP-seq). For the functional analysis, an HPV- HNSCC cell line was transduced with lentiviral constructs containing the two HPV oncogenes (E6 and E7) and effects on methylation were assayed using the Infinium 450k technology. RESULTS AND DISCUSSION: Unsupervised clustering over the most methylation variable positions (MVPs) showed that samples segregated according to HPV status, but also that HPV+ tumours are heterogeneous. MVPs were significantly enriched at transcriptional start sites, leading to the identification of a candidate CpG Island Methylator Phenotype in a sub-group of the HPV+ tumours. Supervised analysis revealed a strong preponderance (87%) of MVPs towards hypermethylation in HPV+ HNSCC. Meta-analysis of our HNSCC and publicly available methylation data in cervical and lung cancer confirmed the observed DNA methylation signature to be HPV-specific and tissue-independent. Grouping of MVPs into functionally more significant differentially methylated regions (DMRs) identified 43 hypermethylated promoter DMRs, including for three Cadherins of the Polycomb group target genes. Integration with independent expression data showed strong negative correlation, especially for the Cadherin gene family members. Combinatorial ectopic expression of the two HPV oncogenes (E6 and E7) in an HPV- HNSCC cell line partially phenocopied the hypermethylation signature observed in HPV+ HNSCC tumours and established E6 as the main viral effector gene. CONCLUSIONS: Our data establish archival FFPE tissue to be highly suitable for this type of methylome analysis and suggest that HPV modulates the HNSCC epigenome through hypermethylation of Polycomb repressive complex 2 target genes such as Cadherins which are implicated in tumour progression and metastasis.

Type: Article
Title: Identification and functional validation of HPV-mediated hypermethylation in head and neck squamous cell carcinoma.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/gm419
Publisher version: http://dx.doi.org/10.1186/gm419
Language: English
Additional information: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention
URI: https://discovery.ucl.ac.uk/id/eprint/1386436
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