Delineating an epigenetic continuum in head and neck cancer

Worsham, Maria J.; Stephen, Josena K.; Chen, Kang Mei; Havard, Shaleta; Shah, Veena; Gardner, Glendon M.; Schweitzer, Vanessa G.

doi:10.1016/j.canlet.2012.02.018

Cited by 33 publications

(38 citation statements)

References 83 publications

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“…Many of these genes were already known to be involved in important functions, including apoptosis, the cell cycle, cell migration, and invasion (for reviews see refs. 28,29). Interestingly, a recent analysis has shown that a protein involved in cell adhesion (cadherin 11) is specifically methylated in metastases (30).…”

Section: Discussionmentioning

confidence: 99%

A Poor Prognosis Subtype of HNSCC Is Consistently Observed across Methylome, Transcriptome, and miRNome Analysis

Jung

Job

Ledrappier

et al. 2013

Clinical Cancer Research

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Purpose: Distant metastasis after treatment is observed in about 20% of squamous cell carcinoma of the head and neck (HNSCC). In the absence of any validated robust biomarker, patients at higher risk for metastasis cannot be provided with tailored therapy. To identify prognostic HNSCC molecular subgroups and potential biomarkers, we have conducted genome-wide integrated analysis of four omic sets of data.Experimental Design: Using state-of-the-art technologies, a core set of 45 metastasizing and 55 nonmetastasizing human papillomavirus (HPV)-unrelated HNSCC patient samples were analyzed at four different levels: gene expression (transcriptome), DNA methylation (methylome), DNA copy number (genome), and microRNA (miRNA) expression (miRNome). Molecular subgroups were identified by a model-based clustering analysis. Their clinical relevance was evaluated by survival analysis, and functional significance by pathway enrichment analysis.Results: Patient subgroups selected by transcriptome, methylome, or miRNome integrated analysis are associated with shorter metastasis-free survival (MFS). A common subgroup, R1, selected by all three omic approaches, is statistically more significantly associated with MFS than any of the single omic-selected subgroups. R1 and non-R1 samples display similar DNA copy number landscapes, but more frequent chromosomal aberrations are observed in the R1 cluster (especially loss at 13q14.2-3). R1 tumors are characterized by alterations of pathways involved in cell-cell adhesion, extracellular matrix (ECM), epithelial-to-mesenchymal transition (EMT), immune response, and apoptosis.Conclusions: Integration of data across several omic profiles leads to better selection of patients at higher risk, identification of relevant molecular pathways of metastasis, and potential to discover biomarkers and drug targets. Clin Cancer Res; 19(15); 4174-84. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

A Poor Prognosis Subtype of HNSCC Is Consistently Observed across Methylome, Transcriptome, and miRNome Analysis

Jung

Job

Ledrappier

et al. 2013

Clinical Cancer Research

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“…Aberrant DNA hypermethylation within gene promoters is a hallmark in various human malignancies, including HNSCC (15)(16)(17), and usually results in downregulation of the associated genes. However, gene silencing via gene promoter methylation is still a novel concept to explain the development of HNSCC; in particular, its effect on the pathogenesis of HPV-driven OPSCC as Supplemental Tables 22 and 23).…”

Section: Introductionmentioning

confidence: 99%

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Kostareli¹,

Holzinger²,

Bogatyrova³

et al. 2013

J. Clin. Invest.

111

130

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High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.

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“…Our group has demonstrated, using high-throughput methods, the contribution of both genetic 1 1 , 1 2 and epigenetic events, 1 3 often working together, 14 in the development and progression of HNSCC. 15 The goal of our study was to examine the status of HPV16 infection and methylation status of IGSF4, DAPK1, and ESR1, candidate genes associated with HNSCC pathogenesis, 14,15 in an OPSCC cohort. 16 …”

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confidence: 99%

IGSF4Methylation as an Independent Marker of Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma

Chen

Stephen

Havard

et al. 2015

JAMA Otolaryngol Head Neck Surg

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Delineating an epigenetic continuum in head and neck cancer

Cited by 33 publications

References 83 publications

A Poor Prognosis Subtype of HNSCC Is Consistently Observed across Methylome, Transcriptome, and miRNome Analysis

A Poor Prognosis Subtype of HNSCC Is Consistently Observed across Methylome, Transcriptome, and miRNome Analysis

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

IGSF4Methylation as an Independent Marker of Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma

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