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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.


Flow chart illustrating the overall design of the study
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Fig1: Flow chart illustrating the overall design of the study

Mentions: The second cohort comprised 278 HNSCC cases from The Cancer Genome Atlas (TCGA) cohort, 36 HPV(+) and 243 HPV(–) [1]. We excluded one HPV(–) case from the original dataset since it was the only tumour localized in the lip. For each case, HM450K data were available and retrieved from the TCGA portal as described in the following sections. The third cohort consisted of 48 oropharyngeal SSCs, 24 HPV(+) and 24 HPV(–) from a study conducted at University College London (UCL) Cancer Institute [2]. Forty-two cases were microdissected from formalin-fixed paraffin-embedded (FFPE) tissues, and 6 were fresh frozen biopsies. Figure 1 shows the overall design of the study.Fig. 1


Unique DNA methylation signature in HPV-positive head and neck squamous cell carcinomas
Flow chart illustrating the overall design of the study
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Flow chart illustrating the overall design of the study
Mentions: The second cohort comprised 278 HNSCC cases from The Cancer Genome Atlas (TCGA) cohort, 36 HPV(+) and 243 HPV(–) [1]. We excluded one HPV(–) case from the original dataset since it was the only tumour localized in the lip. For each case, HM450K data were available and retrieved from the TCGA portal as described in the following sections. The third cohort consisted of 48 oropharyngeal SSCs, 24 HPV(+) and 24 HPV(–) from a study conducted at University College London (UCL) Cancer Institute [2]. Forty-two cases were microdissected from formalin-fixed paraffin-embedded (FFPE) tissues, and 6 were fresh frozen biopsies. Figure 1 shows the overall design of the study.Fig. 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.