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The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

ABSTRACT:

This study was the first-known large-scale effort to uncover the mutational spectrum of head and neck cancers. We analyzed whole-exome sequence from 92 tumor-normal pairs and retained 74 of them for significance analysis. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus sequence was detectable in 15% of cases. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbor mutations in genes (such as NOTCH1, IRF6, TP63) that regulate squamous differentiation, implicating alterations in this process as a major driver of HNSCC carcinogenesis. Altogether, the results suggest that large-scale exome sequencing may illuminate fundamental tumorigenic mechanisms with important therapeutic implications.

PROVIDER: phs000370 | dbGaP |

SECONDARY ACCESSION(S): PRJNA74917PRJNA74919

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs000370.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000370.HeadNeckCancer_Garraway.v1.p1.MULTI.pdf	Pdf
	manifest_phs000370.HeadNeckCancer_Garraway.v1.p1.c1.CRO.pdf	Pdf
	phs000370.v1.p1.HeadNeckCancer_Garraway_SampleInfo.txt	Txt

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The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Project description:This study was the first-known large-scale effort to uncover the mutational spectrum of head and neck cancers. We analyzed whole-exome sequence from 92 tumor-normal pairs and retained 74 of them for significance analysis. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus sequence was detectable in 15% of cases. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbor mutations in genes (such as NOTCH1, IRF6, TP63) that regulate squamous differentiation, implicating alterations in this process as a major driver of HNSCC carcinogenesis. Altogether, the results suggest that large-scale exome sequencing may illuminate fundamental tumorigenic mechanisms with important therapeutic implications.

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Canine Spontaneous Head and Neck Squamous Cell Carcinomas Represent Their Human Counterparts at the Molecular Level.

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Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease whose underlying etiology has not been explained by traditional prognostic factors such as tumor site, stage, or histology. Although previous studies have shown that molecular subtypes of HNSCC exist, the benefit of such a classification scheme has not been fully realized. We show that molecular subtypes of HNSCC exist; that these subtypes have distinct patterns of chromosomal gain and loss, some of which affect canonical oncogenes and tumor suppressors; and that the subtypes are biologically and clinically relevant. These subtypes provide new insight into HNSCC etiology, as well as a valuable method for classifying HNSCC tumors. A total of 163 samples were considered. Quality control procedures were applied to microarray probe-level intensity files. A total of 138 tumor arrays remained after removing low-quality arrays, duplicate arrays, and arrays from non-HNSCC samples. The normexp background correction and loess normalization procedures were applied to the probe-level data. After log transformation, probes were matched to a common gene database to produce expression values for 15595 genes.

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Project description:To identify the activated tyrosine kinase signaling pathways in HNSCC, we carried out phosphotyrosine profiling using a panel of HNSCC cell lines compared to a normal oral keratinocyte. A total of 61 unique phosphosites were identified across these cell lines. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Y321 in all the HNSCC cell lines compared to the normal oral cell line OKF6/TERT1. Inhibition of DYRK1A using its specific siRNA and inhibitor resulted in a decrease in the invasion and colony formation ability of the HNSCC cell lines. Further, the treatment of mice bearing HNSCC xenograft tumors with DYRK1A inhibitor (harmine) showed regression of tumor growth. Our results demonstrate that DYRK1A could be a novel therapeutic target in HNSCC.

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Project description:The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of public available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regualted genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Our findings reveal that BRD4 serves as a novel oncogene driving cancer progression and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.

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Molecular Subtypes in Head and Neck Cancer [expression]

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Project description:This study represents a proteomic resource for HNSCC and SQCLC with quantitative protein expression data for 7800 proteins and provides a proteomic diagnostic signature for classification for undetermined secondary lung tumors in HNSCC patients. By quantitative mass-spectrometry-based proteomics, we characterized a cohort of 63 squamous cell carcinomas of the lung (SQCLC), 49 of the head and neck region (HNSCC) and 51 HNSCC-correlated lung tumors with squamous cell histology that evolved in the course of the disease.

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Expression data from head and neck squamous cell carcinoma

Project description:Forty-four paired (from the same patient) samples of head and neck squamous cell carcinoma (HNSCC) and normal tissue were studied with Affymetrix U95A chips. A stringent multi-test approach, combining 7 traditional and microarray-specific statistical tests, was used to analyze the resultant data. Candidate genes were assigned to tiers of significance based on the number of statistical tests that each gene satisfied. Representative genes (both up-regulated and down-regulated) from each of the 3 tiers would be quantified with RT-PCR on both microarray-tested and new samples of HNSCC. The goal of this study is to identify reliable differentially-expressed genes on HNSCC and to testify our hypothesis whether or not a combinatorial approach (multi-tests) to analyzing microarray data can really identify differentially-expressed genes with fewer false-positives. Keywords: disease state; tumor vs. normal

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Molecular Subtypes in Head and Neck Cancer [copy number]

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Project description:There is a pressing need to improve risk stratification and treatment selection for HPV-negative head and neck squamous cell carcinoma (HNSCC) due to the adverse side effects of treatment. One of the most important prognostic features is metastases in lymph nodes. Previously, we demonstrated that tumor formation in patient-derived xenografts (i.e. engraftment) was associated with poor clinical outcomes in patients with HPV-negative HNSCC. However, assessing engraftment is challenging to implement in clinical settings. Here, we performed transcriptomic and proteomic profiling of 88 HNSCC patients and found the relationship between engraftment and clinical outcomes was recapitulated by molecular phenotype. We identified LAMC2 and TGM3 as candidate prognostic biomarkers and validated their utility in an independent cohort containing 404 HPV-negative HNSCC patients. Strikingly, these markers significantly improve prediction of outcomes beyond nodal status alone and can significantly stratify patients without any nodal involvement. Overall, our study demonstrates how the molecular characteristics of engraftment can inform patient prognostication.

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