Molecular diagnostic alterations in squamous cell carcinoma of the head and neck and potential diagnostic applications

Hunt, Jennifer L.; Barnes, Leon; Lewis, James S.; Mahfouz, Magdy E.; Slootweg, Pieter J.; Thompson, Lester D.�R.; Cardesa, Antonio; Devaney, Kenneth O.; Gnepp, Douglas R.; Westra, William H.; Rodrigo, Juan P.; Woolgar, Julia A.; Rinaldo, Alessandra; Triantafyllou, Asterios; Takes, Robert P.; Ferlito, Alfio

doi:10.1007/s00405-013-2400-9

Cited by 26 publications

(27 citation statements)

References 147 publications

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“…The other common alteration identified in this panel is a specific MET variant (MET N357S), identified in 10.6% (7/66) of this cohort [44, 45]. The therapeutic role for inhibiting the MET pathway has yet to be validated, and several trials evaluating targeting MET are ongoing [46–48].…”

Section: Discussionmentioning

confidence: 99%

Tongue carcinoma infrequently harbor common actionable genetic alterations

et al. 2014

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BackgroundOral tongue squamous cell carcinomas (TSCC) are a unique subset of head and neck cancers with a distinct demographic profile, where up to half of the cases are never smokers. A small proportion of patients with OSCC are known to respond to EGFR TKI. We used a high-sensitivity mass spectrometry-based mutation profiling platform to determine the EGFR mutation status, as well as other actionable alterations in a series of Asian TSCC.Methods66 TSCC patients treated between 1998-2009 with complete clinico-pathologic data were included in this study. Somatic mutation profiling was performed using Sequenom LungCarta v1.0, and correlated with clinical parameters.ResultsMutations were identified in 20/66(30.3%) of samples and involved TP53, STK11, MET, PIK3CA, BRAF and NRF2. No activating EGFR mutations or KRAS mutations were discovered in our series, where just over a third were never smokers. The most common mutations were in p53 (10.6%; n = 7) and MET (10.6%, n = 11) followed by STK11 (9.1%, n = 6) and PIK3CA (4.5%, n = 3). BRAF and NRF2 mutations, which are novel in TSCC, were demonstrated in one sample each. There was no significant correlation between overall mutation status and smoking history (p = 0.967) or age (p = 0.360). Positive MET alteration was associated with poorer loco-regional recurrence free survival (LRFS) of 11 months [vs 90 months in MET-negative group (p = 0.008)]. None of the other mutations were significantly correlated with LRFS or overall survival. Four of these tumors were propagated as immortalized cell lines and demonstrated the same mutations as the original tumor.ConclusionsUsing the Sequenom multiplexed LungCarta panel, we identified mutations in 6 genes, TP53, STK11, MET, PIK3CA, BRAF and NRF2, with the notable absence of EGFR and HER2 mutations in our series of Asian OSCC. Primary cell line models recapitulated the mutation profiles of the original primary tumours and provide an invaluable resource for experimental cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

Tongue carcinoma infrequently harbor common actionable genetic alterations

et al. 2014

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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%

“…Molecular alterations are starting to directly affect the approach to patient care and are currently the subject of investigation in numerous clinical trials [15,16]. We wanted to explore the potential efficacy of implementing higher throughput strategies that combine targeted differential gene expression mutation profiling to help improve stratification of SCCHN by risk categories for both HPV-positive and negative disease.…”

Section: Introductionmentioning

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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“…These genes have significant consequences on the efficacy of targeted therapeutic strategies. 9 Oncogenes are critical tumour-associated genes, with tumours often driven by only one oncogene mutation -the so called 'oncogene addiction'. 10 Epidermal growth factor receptor is overexpressed in more than 90 per cent of head and neck squamous cell carcinoma (SCC) cases, and its over expression is associated with poor treatment outcomes.…”

Section: Corrective Strategiesmentioning

confidence: 99%