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

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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

No MeSH data available.


DNA methylation changes associated with gene expression changes in the TCGA cohort. Starburst plot showing correlations between gene expression changes and DNA methylation changes in DMRs with Δβ >20%. Red dots indicate up-regulated genes in HPV(+) cases with a minimum logFC >1. Purple dots indicate down-regulated genes with a minimum logFC < –1. Grey dots indicate genes with expression changes –1 < logFC < 1 and changes in methylation with Δβ >20%
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Fig4: DNA methylation changes associated with gene expression changes in the TCGA cohort. Starburst plot showing correlations between gene expression changes and DNA methylation changes in DMRs with Δβ >20%. Red dots indicate up-regulated genes in HPV(+) cases with a minimum logFC >1. Purple dots indicate down-regulated genes with a minimum logFC < –1. Grey dots indicate genes with expression changes –1 < logFC < 1 and changes in methylation with Δβ >20%

Mentions: In order to investigate potential functional effects of DNA hypomethylation in these regions, we first plotted gene expression log2 fold changes (log2FC) and DNA methylation changes (Δβmax >20%) of the genes belonging to the DMRs found with a Δβmax >20%. Gene expression data were available for 165 genes (105 hypomethylated and 60 hypermethylated) for the TCGA cohort and were extracted from the cBioPortal. We found that 49 out of 105 genes located in hypo-DMRs showed an increased gene expression (log2FC >2), while 15 out of 60 genes located in hyper-DMRs showed decreased gene expression (log2FC <2) (p value < 0.006, χ2 test) (Fig. 4). We then systematically analysed the 50 most differentially methylated regions (Stouffer FDR <0.05; ranked by Δβmax). Similarly, we found a significant correlation (Pearson, p value < 0.05) between average DNA methylation levels and gene expression in 52% (13 out of 25 cases) of the genes located in hypo-DMRs and in 4% (1 out of 25 cases, ZNF733) of the genes located in hyper-DMRs (p value < 0.001, χ2 test) (TCGA dataset) (Additional file 9).Fig. 4


Unique DNA methylation signature in HPV-positive head and neck squamous cell carcinomas
DNA methylation changes associated with gene expression changes in the TCGA cohort. Starburst plot showing correlations between gene expression changes and DNA methylation changes in DMRs with Δβ >20%. Red dots indicate up-regulated genes in HPV(+) cases with a minimum logFC >1. Purple dots indicate down-regulated genes with a minimum logFC < –1. Grey dots indicate genes with expression changes –1 < logFC < 1 and changes in methylation with Δβ >20%
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5382363&req=5

Fig4: DNA methylation changes associated with gene expression changes in the TCGA cohort. Starburst plot showing correlations between gene expression changes and DNA methylation changes in DMRs with Δβ >20%. Red dots indicate up-regulated genes in HPV(+) cases with a minimum logFC >1. Purple dots indicate down-regulated genes with a minimum logFC < –1. Grey dots indicate genes with expression changes –1 < logFC < 1 and changes in methylation with Δβ >20%
Mentions: In order to investigate potential functional effects of DNA hypomethylation in these regions, we first plotted gene expression log2 fold changes (log2FC) and DNA methylation changes (Δβmax >20%) of the genes belonging to the DMRs found with a Δβmax >20%. Gene expression data were available for 165 genes (105 hypomethylated and 60 hypermethylated) for the TCGA cohort and were extracted from the cBioPortal. We found that 49 out of 105 genes located in hypo-DMRs showed an increased gene expression (log2FC >2), while 15 out of 60 genes located in hyper-DMRs showed decreased gene expression (log2FC <2) (p value < 0.006, χ2 test) (Fig. 4). We then systematically analysed the 50 most differentially methylated regions (Stouffer FDR <0.05; ranked by Δβmax). Similarly, we found a significant correlation (Pearson, p value < 0.05) between average DNA methylation levels and gene expression in 52% (13 out of 25 cases) of the genes located in hypo-DMRs and in 4% (1 out of 25 cases, ZNF733) of the genes located in hyper-DMRs (p value < 0.001, χ2 test) (TCGA dataset) (Additional file 9).Fig. 4

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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

No MeSH data available.