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

Abstract

BackgroundHead 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0419-z) contains supplementary material, which is available to authorized users.

Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors

“…Silenced targets included previously reported targets of recurrent hyper-methylation such as MLH1, BRCA1, FANCF, and CHFR (Lahtz and Pfeifer, 2011;Cancer Genome Atlas Research Network, 2011;Cancer Genome Atlas Network, 2012;Toyota et al, 2003) and other cancer-associated genes including the cell-cycle-regulator CDKN1C, the transforming growth factor b (TGF-b) signaling genes TGIF1 and ACVR1C, and the pro-apoptotic genes FAS, BIRC3, TNFRSF1A, and TNFRSF10A. Similarly, epigenetically enhanced targets included positive controls such as MAGEC2 (Van Tongelen et al, 2017) and SYCP2 (Degli Esposti et al, 2017), and known oncogenes, such as MYCN, BCL2L10, CTNNB1, IRS2, and IGF2. Only 3 out of 581 silenced and 3 out 85 enhanced target genes showed significant associations between their alteration patterns and the estimated fraction of infiltrated non-tumor cells (q value <0.1, fold-change >1.5, Table S4) and, for each gene, this association was found only within one tumor type.…”

Stratification of HPV‐associated and HPV‐negative oropharyngeal squamous cell carcinomas based on DNA methylation epigenotypes

“…19,38 This could be because only a few epigenome analyses had focused solely on OPSCC, and even with these, the cohort size was small. [43][44][45] We here performed DNA methylation analysis of the largest OPSCC cohort on a genome-wide scale, and 170 OPSCC cases were successfully classified into four epigenotypes reflecting the prognostic status, while TNM stage did not correlate with prognosis. While there have been no molecular markers available that clinically distinguish low-risk patients from intermediate-risk patients in HPV-associated OPSCC, we here established highly accurate classifier marker panels to easily categorize OPSCC into distinct epigenotypes.…”

The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome

“…Following the frequent inclusion of epigenetics as a parameter in environmental epidemiology studies, numerous reports have been made in recent years associating alterations in DNA methylation with various environmental factors, including biological agents, dietary habits, and air pollution (Ambatipudi et al 2016;Barouki et al 2018;de FC Lichtenfels et al 2018;Degli Esposti et al 2017;Fasanelli et al 2019;Feil and Fraga 2012;Hattori and Ushijima 2016;Herceg et al 2018;Martin and Fry 2018;Perrier et al 2019;Woo et al 2018). Similarly, many reports indicate that microRNA (miRNA) profiles are responsive to various environmental exposures, including air pollution ; Espín-Pérez et al (2018), both epidemiological studies], nanoparticles [Brzóska et al (2019), utilizing human liver cells], endocrine disruptors, such as bisphenol A (BPA) [Chou et al (2017), using human endometrial cells, and Martínez-Ibarra et al (2019), using human blood samples], and dichlorodiphenyltrichloroethane (DDT) [Krauskopf et al (2017), using human blood].…”