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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.


Related in: MedlinePlus

HPV infection leaves clear DNA methylation signature in HNSCCs. MDS plots showing sample clustering grouped by different variables: a HPV status, b organ site, c smoking status, d alcohol consumption. e Heatmap showing the 2410 DMPs associated with HPV status (FDR <0.05, Δβ >20%)
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Fig2: HPV infection leaves clear DNA methylation signature in HNSCCs. MDS plots showing sample clustering grouped by different variables: a HPV status, b organ site, c smoking status, d alcohol consumption. e Heatmap showing the 2410 DMPs associated with HPV status (FDR <0.05, Δβ >20%)

Mentions: To address the impact of HPV infection on the DNA methylome in HNSCC with greater power, we collated two major studies with raw DNA methylome data [1, 2] and performed additional methylome analyses of 6 HPV(+) and 6 HPV(–) HNSCC samples from a smaller independent French cohort (FITMANET). Thus, in the analysis we included the methylome data from different geographical regions with a total of 338 cases, among which 66 were HPV(+) (Table 1, Fig. 1). After applying stringent quality-control filters (see Methods section), we analysed the methylome of 326 cases, of which 63 were HPV(+). An initial multidimensional scaling (MDS) analysis, using normalized logit-transformed methylation values for the most variable probes (4500 probes) to calculate their Euclidean distance, showed that cancer samples from the three datasets clustered clearly in two separate groups based on their HPV status (Fig. 2a, Additional file 2: Figure S1A–C). Importantly, these clusters did not associate with anatomic site, smoking habits and alcohol consumption (Fig. 2b–d).Table 1


Unique DNA methylation signature in HPV-positive head and neck squamous cell carcinomas
HPV infection leaves clear DNA methylation signature in HNSCCs. MDS plots showing sample clustering grouped by different variables: a HPV status, b organ site, c smoking status, d alcohol consumption. e Heatmap showing the 2410 DMPs associated with HPV status (FDR <0.05, Δβ >20%)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5382363&req=5

Fig2: HPV infection leaves clear DNA methylation signature in HNSCCs. MDS plots showing sample clustering grouped by different variables: a HPV status, b organ site, c smoking status, d alcohol consumption. e Heatmap showing the 2410 DMPs associated with HPV status (FDR <0.05, Δβ >20%)
Mentions: To address the impact of HPV infection on the DNA methylome in HNSCC with greater power, we collated two major studies with raw DNA methylome data [1, 2] and performed additional methylome analyses of 6 HPV(+) and 6 HPV(–) HNSCC samples from a smaller independent French cohort (FITMANET). Thus, in the analysis we included the methylome data from different geographical regions with a total of 338 cases, among which 66 were HPV(+) (Table 1, Fig. 1). After applying stringent quality-control filters (see Methods section), we analysed the methylome of 326 cases, of which 63 were HPV(+). An initial multidimensional scaling (MDS) analysis, using normalized logit-transformed methylation values for the most variable probes (4500 probes) to calculate their Euclidean distance, showed that cancer samples from the three datasets clustered clearly in two separate groups based on their HPV status (Fig. 2a, Additional file 2: Figure S1A–C). Importantly, these clusters did not associate with anatomic site, smoking habits and alcohol consumption (Fig. 2b–d).Table 1

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.


Related in: MedlinePlus