Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas

Papillon‐Cavanagh, Simon; Lü, Chao; Gayden, Tenzin; Mikael, Leonie G.; Béchet, Denise; Karamboulas, Christina; Ailles, Laurie; Karamchandani, Jason; Marchione, Dylan M.; Garcia, Benjamin A.; Weinreb, Ilan; Goldstein, David P.; Lewis, Peter W.; Dancu, Octavia Maria; Dhaliwal, Sandeep; Stecho, William; Howlett, Christopher J.; Mymryk, Joe S.; Barrett, John W.; Nichols, Anthony C.; Allis, C. David; Majewski, Jacek; Jabado, Nada

doi:10.1038/ng.3757

Cited by 205 publications

(228 citation statements)

References 48 publications

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“…Globally, our results show that HPV has a specific and genome-wide effect in shaping the DNA methylome of HNSCCs that is independent of other known major risk factors, such as tobacco smoking and alcohol consumption. Our results are similar to a recent report based on the analysis of the whole TCGA cohort [29]. The authors identified five subclusters of HNSSC based on DNA methylation patterns (528 samples), four HPV(–) clusters and one HPV(+) cluster [29].…”

Section: Discussionsupporting

confidence: 90%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 90%

“…Our results are similar to a recent report based on the analysis of the whole TCGA cohort [29]. The authors identified five subclusters of HNSSC based on DNA methylation patterns (528 samples), four HPV(–) clusters and one HPV(+) cluster [29]. …”

Section: Discussionsupporting

confidence: 90%

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

et al. 2017

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“…Among 28/51 genes significantly mutated and differentially distributed among the methylation clusters in SCC (Table S2L), hypermethylated HPV-enriched C2 also harbored fewer mutations in HRAS , CDKN2A(p16) , CASP8 , NFE2L2 , NSD1 , and TP53 than did clusters with predominantly HPV(−) SCC (Figures 4A and S3B). Strikingly, hypomethylation in C5 was linked to inactivating mutations in the H3K36 histone methyltransferase NSD1, defining a distinct subtype across SCC tissue sites previously observed in HNSC (Cancer Genome Atlas Network, 2015; Papillon-Cavanagh et al, 2017). …”

Section: Resultsmentioning

confidence: 72%

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Campbell¹,

Yau²,

Bowlby³

et al. 2018

Cell Reports

267

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SUMMARY This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

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“…5, Supplementary Table 4), consistent with our previous report (Gevaert et al, 2015). Our NSD1-Smoking subtype corresponding to the H3K36me-impared subtype of HNSCC reported by Papillon-Cavanagh et al (2017). Thirty percent of patients within the CIMP-Atypical subtype featured CASP8 mutations, compared with 0–7% in other subtypes, a highly significant enrichment (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 73%

Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype

et al. 2017

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Head and neck squamous cell carcinoma (HNSCC) is broadly classified into HNSCC associated with human papilloma virus (HPV) infection, and HPV negative HNSCC, which is typically smoking-related. A subset of HPV negative HNSCCs occur in patients without smoking history, however, and these etiologically ‘atypical’ HNSCCs disproportionately occur in the oral cavity, and in female patients, suggesting a distinct etiology.To investigate the determinants of clinical and molecular heterogeneity, we performed unsupervised clustering to classify 528 HNSCC patients from The Cancer Genome Atlas (TCGA) into putative intrinsic subtypes based on their profiles of epigenetically (DNA methylation) deregulated genes.HNSCCs clustered into five subtypes, including one HPV positive subtype, two smoking-related subtypes, and two atypical subtypes. One atypical subtype was particularly genomically stable, but featured widespread gene silencing associated with the ‘CpG island methylator phenotype’ (CIMP).Further distinguishing features of this ‘CIMP-Atypical’ subtype include an antiviral gene expression profile associated with pro-inflammatory M1 macrophages and CD8+ T cell infiltration, CASP8 mutations, and a well-differentiated state corresponding to normal SOX2 copy number and SOX2OT hypermethylation. We developed a gene expression classifier for the CIMP-Atypical subtype that could classify atypical disease features in two independent patient cohorts, demonstrating the reproducibility of this subtype. Taken together, these findings provide unprecedented evidence that atypical HNSCC is molecularly distinct, and postulates the CIMP-Atypical subtype as a distinct clinical entity that may be caused by chronic inflammation.

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Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas

Cited by 205 publications

References 48 publications

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

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

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype

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