Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma

Lleras, Roberto A.; Smith, Richard V.; Adrien, Leslie R.; Schlecht, Nicolas F.; Burk, Robert D.; Harris, Thomas M.; Childs, Geoffrey; Prystowsky, Michael B.; Belbin, Thomas J.

doi:10.1158/1078-0432.ccr-12-3280

Cited by 83 publications

(120 citation statements)

References 49 publications

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“…Previous work has shown that HPV-positive tumors have a distinct methylation profile compared with HPV-negative tumors (43,44). To study the influence of HPV integration events on the host cell, we compared the patterns of DNA methylation and gene expression of HNSCCs with and without integration.…”

Section: Hpv Integration Is Associated With a Specific Methylation Simentioning

confidence: 99%

Characterization of HPV and host genome interactions in primary head and neck cancers

Parfenov¹,

Pedamallu²,

Gehlenborg³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

342

474

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Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twentyfive cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter-and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.cancer | head and neck | papilloma virus | genome rearrangement | integration sites H ead and neck cancer (HNC) is a heterogeneous group of tumors characterized by a common anatomic origin, and most such tumors develop from within the mucosa and are classified as head and neck squamous cell carcinomas (HNSCCs) (1). HNSCC, the sixth most common cancer diagnosed worldwide and the eighth most common cause of cancer death (2), is frequently associated with human papillomavirus (HPV) infection (3, 4). Depending on the anatomic site of the tumor, HPV prevalence is estimated at 23-36% (5). HPV-positive HNSCCs form a distinct subset of HNCs that differs from HPV-negative HNSCCs in tumor biology and clinical characteristics, including superior clinical outcomes (6-9).The molecular pathogenesis of HPV-driven HNSCC also seems distinct from HPV-negative tumors, with previous studies showing a divergent spectrum of alterations in gene expression, mutations, amplifications, and deletions as well as distinct epigenome alterations (10-15). HPV is known to drive tumorigenesis through the actions of its major oncoproteins E6 and E7, which target numerous cellular pathways, including inactivation of p53 and the retinoblastoma (Rb) protein (16-18). Together with E5, they also play an important role in immune evasion, being involved in both innate and adaptive immunity (19,20).Initially after infection, HPV is identified in circular extrachromosomal particles or episomes. A critical step in progression to cancer is the integration of viral DNA into the host cell Significance A significant proportion of head and neck cancer is driven by human papil...

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Section: Hpv Integration Is Associated With a Specific Methylation Simentioning

confidence: 99%

Characterization of HPV and host genome interactions in primary head and neck cancers

Parfenov¹,

Pedamallu²,

Gehlenborg³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

342

474

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“…In addition, The Cancer Genome Atlas (TCGA) head and neck study found that TNF receptor-associated factor 3 (TRAF3) and CYLD genes are commonly mutated and deleted in HPV þ HNSCC (6,8,14). Finally, HPV À HNSCC have relatively low levels of DNA methylation, which is correlated with genomic instability (15), whereas HPV þ HNSCC harbor distinctly hypermethylated genomes (7,8,16,17). Demographic, clinical, molecular, and epigenetic differences between HPV þ and HPV À HNSCC suggest two distinct cancers, yet HPV À status is currently only used for prognosis and not to guide treatment (18).…”

mentioning

confidence: 99%

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Biktasova

Hajek

Sewell

et al. 2017

Clinical Cancer Research

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Purpose: DNA methylation in human papillomavirus-associated (HPV þ ) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV þ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV þ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV þ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV þ HNSCC. classically associated with tobacco and alcohol exposure, including loss-of-function mutations of TP53 (84%) and loss or inactivating mutations of CDKN2A (54%). In contrast, genetic alterations in these genes are extremely rare in the HPV þ subset (TP53, 3%; CDKN2A, 0%; ref. 6), which instead is associated with a mutational signature typical of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) antiviral proteins (6, 11-13). In addition, The Cancer Genome Atlas (TCGA) head and neck study found that TNF receptor-associated factor 3 (TRAF3) and CYLD genes are commonly mutated and deleted in HPV þ HNSCC (6,8,14). Finally, HPV À HNSCC have relatively low levels of DNA methylation, which is correlated with genomic instability (15), whereas HPV þ HNSCC harbor distinctly hypermethylated genomes (7,8,16,17). Demographic, clinical, molecular, and epigenetic differences between HPV þ and HPV À HNSCC suggest two distinct cancers, yet HPV À status is currently only used for prognosis and not to guide treatment (18). A majority of HNSCC patients are treated with radiation and platin-based chemotherapy, which is associated with deleterious and lifelong side-effects. Despite the relatively good prognosis associated with HPV þ HNSCC, 25%-30% of patients with HPV-positive tumors experience recurrent or metastatic disease, for which treatment options are limited. The molecular and epigenetic differences between HPV þ and HPV À tumors provide an opportunity for therapies that exploit the interaction of the HPV genome and host that result in hypermethylation of cancer cell genomes. 5-Azacytidine (5-aza)

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“…9 Proteomics This article has touched on methodologies and bioinformatics in genomics and epigenetics. Proteomics, the comprehensive evaluation of protein expression, structure, modification and function in biological systems, deserves brief mention here.…”

Section: Single Nucleotide Polymorphism Arraysmentioning

confidence: 99%

“…18 In a study from our own institution, DNA methylation arrays were performed on 118 head and neck SCC tumour-normal pairs. 9 Differentially methylated genes could distinguish between head and neck SCC and normal tissue. Methylation events specific to tumour subsite and to HPV status were also identified.…”

Section: Single Nucleotide Polymorphism Arraysmentioning

confidence: 99%

“…The expression levels of three highly methylated genes seen in head and neck SCC tumors, ZNF132, ZNF154, and UCHL-1, were then evaluated in an available corresponding gene expression dataset, and these genes were found to be consistently down-regulated. 9 Combining data from two platforms is challenging, but a truly integrated approach involves analysing gene networks from data on multiple platforms, exploring genetic alterations, epigenetic regulation and gene transcription in a comprehensive manner. The field of systems biology, as applied to cancer research, aims to use a holistic approach, simultaneously incorporating data from several disciplines in order to evaluate cell signalling networks and model systems, so as to better understand the determinants of cancer cell function, behaviour and phenotype.…”

Section: Single Nucleotide Polymorphism Arraysmentioning

confidence: 99%

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Bioinformatics in otolaryngology research. Part two: other high-throughput platforms in genomics and epigenetics

Upadhyay

Belbin

et al. 2014

J. Laryngol. Otol.

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Objectives: This second segment of the two-part review summarises several modern high-throughput methods in genomics, epigenetics and molecular biology. Many principles from nucleotide sequencing and transcriptomics can be applied to other high-throughput molecular biology techniques. Specifically, this manuscript reviews: array comparative genome hybridisation; single nucleotide polymorphism arrays; microarray technology, used to study epigenetics; and methodology applied in proteomics. Finally, the review describes current methods for the integration of multiple molecular biology platforms.Conclusion: Progress in treating human disease in general will require close collaboration with experts in bioinformatics. Improved understanding, by clinicians and physician-scientists in our field, of the concepts presented in both parts of this review will advance diagnosis and therapy for diseases of the head and neck.

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Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma

Cited by 83 publications

References 49 publications

Characterization of HPV and host genome interactions in primary head and neck cancers

Characterization of HPV and host genome interactions in primary head and neck cancers

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Bioinformatics in otolaryngology research. Part two: other high-throughput platforms in genomics and epigenetics

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