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

Jung, Alain C.; Job, Sylvie; Ledrappier, Sonia; Macabre, Christine; Abecassis, Joseph; Reyniès, Aurélien de; Wasylyk, Bohdan

doi:10.1158/1078-0432.ccr-12-3690

Cited by 45 publications

(46 citation statements)

References 50 publications

(55 reference statements)

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“…However, these technologies have had little impact on standard methods for diagnosis and treatment of HNSCC and many other types of cancer with one or more known mutational or copy number drivers. Despite extensive literature of differential gene expression profiles, mutations and copy number abnormalities in head and neck tumors that could potentially impact future clinical applications, little other than HPV status is done routinely upon diagnosis [7,10,11,13,15,24,32,[35][36][37][38][39][40][41][42][43][44][45][46][47]. A main factor contributing to this lack of progress is that no clear directives or actionable guidelines have been adopted for molecularly profiling HNSCCs.…”

Section: Discussionmentioning

confidence: 99%

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Saba

Wilson

Doho

et al. 2014

Head and Neck Pathol

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The role of molecular methods in the diagnosis of head and neck cancer is rapidly evolving and holds great potential for improving outcomes for all patients who suffer from this diverse group of malignancies. However, there is considerable debate as to the best clinical approaches, particularly for Next Generation Sequencing (NGS). The choices of NGS methods such as whole exome, whole genome, whole transcriptomes (RNA-Seq) or multiple gene resequencing panels, each have strengths and weakness based on data quality, the size of the data, the turnaround time for data analysis, and clinical actionability. There have also been a variety of gene expression signatures established from microarray studies that correlate with relapse and response to treatment, but none of these methods have been implemented as standard of care for oropharyngeal squamous cell carcinoma (OPSCC). Because many genomic methodologies are still far from the capabilities of most clinical laboratories, we chose to explore the use of a combination of off the shelf targeted mutation analysis and gene expression analysis methods to complement standard anatomical pathology methods. Specifically, we have used the Ion Torrent AmpliSeq cancer panel in combination with the NanoString nCounter Human Cancer Reference Kit on 8 formalin-fixed paraffin embedded (FFPE) OPSCC tumor specimens, (4) HPVpositive and (4) HPV-negative. Differential expression analysis between HPV-positive and negative groups showed that expression of several genes was highly likely to correlate with HPV status. For example, WNT1, PDGFA and OGG1 were all over-expressed in the positive group. Our results show the utility of these methods with routine FFPE clinical specimens to identify potential therapeutic targets which could be readily applied in a clinical trial setting for clinical laboratories lacking the instrumentation or bioinformatics infrastructure to support comprehensive genomics workflows. To the best of our knowledge, these preliminary experiments are among the earliest to combine both mutational and gene expression profiles using Ion Torrent and NanoString technologies. This reports serves as a proof of principle methodology in OPSCC.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Saba

Wilson

Doho

et al. 2014

Head and Neck Pathol

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“…Furthermore, the complementarity among the various "omes" of HNSCC appears to offer an unparalleled opportunity for integration to achieve improved patient classification. In fact, a recent study has demonstrated the exquisite prognostic utility of 3p loss and TP53 mutations to classify HNSCCs (56,57). Underrepresentation of oropharyngeal cancers, particularly HPV þ tumors, is one potential caveat of these molecular investigations.…”

Section: Summary and Future Perspectivementioning

confidence: 99%

Novel Insights into Head and Neck Cancer using Next-Generation “Omic” Technologies

et al. 2015

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Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease that develops via one of the two primary carcinogenic routes: chemical carcinogenesis through exposure to tobacco and alcohol or virally induced tumorigenesis. Human papillomavirus (HPV)-positive (HPV þ ) and HPV-negative (HPV À ) HNSCCs represent distinct clinical entities, with the latter associated with significantly inferior outcome. The biologic basis of these different outcomes is an area of intense investigation; their therapeutic regimens are currently also being reevaluated, which would be significantly facilitated by reliable biomarkers for stratification. With the advent of the omics era and accelerated development of targeted therapies, there are unprecedented opportunities to address the challenges in the management of HNSCC. As summarized herein, side-by-side molecular characterization of HPV þ versus HPV À HNSCC has revealed distinct molecular landscapes, novel prognostic signatures, and potentially targetable biologic pathways. In particular, we focus on the evidence acquired from genome-wide omics pertinent to our understanding of the clinical behavior of HNSCC and on insights into personalized treatment opportunities. Integrating, mining, and validating these data toward clinically meaningful outcomes for patients with HNSCC in conjunction with systematic verification of the functional relevance of these findings are critical steps toward the design of personalized therapies. Cancer Res; 75(3); 480-6. Ó2014 AACR. Oncogenic Role of Human PapillomavirusesHigh-risk human papillomaviruses (HPV) are double-stranded DNA viruses that infect epithelial cells (1). Tumorigenesis by high-risk HPVs is driven by their two main viral oncogenes, E6 and E7, which inactivate p53 and pRb, respectively, leading to cellcycle deregulation and inhibition of p53-mediated apoptosis (1, 2). E7 binds pRb, targeting it toward proteosomal degradation, in turn releasing the E2F transcription factor, resulting in CDKN2A (or p16) overexpression and cell-cycle progression (1).High-risk HPVs, predominantly types 16, 18, 31, 33, and 35, are estimated to cause approximately 5% of cancers worldwide, including 99% of cervical, 25% of head and neck (or 60% oropharyngeal), 70% of vaginal, 88% of anal, 43% of vulvar, and 50% of penile cancers, in order of prevalence (1-6). A significant subset of approximately 500,000 annual cases of head and neck squamous cell carcinoma (HNSCC) include approximately 85,000 HPV-associated tumors, establishing this as the second most common HPV-associated tumor site (3, 4). HPV type 16 is identified in over 90% of HPV-associated HNSCCs (4). The majority of the remaining HNSCCs are attributed to exposure to chemical carcinogens such as tobacco and alcohol.HPV-positive (HPV þ ) and HPV-negative (HPV À ) HNSCCs are separate entities associated with distinct etiology, clinical behavior, treatment outcomes, imaging and pathology appearance, and molecular profiles (2, 7). HPV þ HNSCC primarily involves the oropharynx (pr...

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“…We previously showed that the "R1" cluster of patient was characterized by alterations of pathways involved in EMT [6]. In accordance, a significant reduction of E-cadherin expression and an increase of the vimentin/E-cadherin ratio were found in "R1" patients compared to "non-R"1 tumours.…”

Section: Impactjournalscom/oncotargetmentioning

confidence: 57%

“…The way tumor cells interact with and modify their environment is a key issue in the acquisition of metastatic properties. In accordance, "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 [6]. Similarly, alterations of genes controlling adhesion, motility and invasiveness especially integrins were reported as the major molecular differences among metastatic and nonmetastatic HNSCC tumors [7][8][9].…”

Section: Introductionmentioning

confidence: 96%

Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties

Martin¹,

Jung²,

Ray³

et al. 2016

European Journal of Cancer

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

Cited by 45 publications

References 50 publications

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Novel Insights into Head and Neck Cancer using Next-Generation “Omic” Technologies

Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties

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