Unique DNA methylation signature in HPV-positive head and neck squamous cell carcinomas

Davide Degli Esposti, Athena Sklias, Sheila C. Lima, Stéphanie Beghelli-de la Forest Divonne, Vincent Cahais, Nora Fernandez-Jimenez, Marie-Pierre Cros, Szilvia Ecsedi, Cyrille Cuenin, Liacine Bouaoun, Graham Byrnes, Rosita Accardi, Anne Sudaka, Valérie Giordanengo, Hector Hernandez-Vargas, Luis Felipe Ribeiro Pinto, Ellen Van Obberghen-Schilling, Zdenko Herceg

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of cancers for which human papilloma virus (HPV) infection is an emerging risk factor. Previous studies showed promoter hypermethylation in HPV(+) oropharyngeal cancers, but only few consistent target genes have been so far described, and the evidence of a functional impact on gene expression is still limited. We performed global and stratified pooled analyses of epigenome-wide data in HNSCCs based on the Illumina HumanMethylation450 bead-array data in order to identify tissue-specific components and common viral epigenetic targets in HPV-associated tumours. We identified novel differentially methylated CpGs and regions associated with viral infection that are independent of the anatomic site. In particular, most hypomethylated regions were characterized by a marked loss of CpG island boundaries, which showed significant correlations with expression of neighbouring genes. Moreover, a subset of only five CpGs in a few hypomethylated regions predicted HPV status with a high level of specificity in different cohorts. Finally, this signature was a better predictor of survival compared with HPV status determined by viral gene expression by RNA sequencing in The Cancer Genome Atlas cohort. We identified a novel epigenetic signature of HPV infection in HNSCCs which is independent of the anatomic site, is functionally correlated with gene expression and may be leveraged for improved stratification of prognosis in HNSCCs.