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      Genomics and advances towards precision medicine for head and neck squamous cell carcinoma

      , MD, PhD , 1 , , BEng(Hons), MBBS 1

      Laryngoscope Investigative Otolaryngology

      John Wiley and Sons Inc.

      Clinical Trials, Genomics, Head and Neck Cancer, Molecular Targeted Therapy

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          To provide a review of emerging knowledge from genomics and related basic science, preclinical, and clinical precision medicine studies in head and neck squamous cell carcinoma (HNSCC).

          Data Sources

          The Cancer Genome Atlas Network (TCGA) publications, PubMed‐based literature review, and

          Review Methods

          TCGA publications, PubMed, and were queried for genomics and related basic science, preclinical, and developmental clinical precision medicine studies in HNSCC.


          TCGA reported comprehensive genomic analyses of 279 HNSCC, defining the landscape and frequency of chromosomal copy number alterations, mutations, and expressed genes that contribute to pathogenesis, prognosis, and resistance to therapy. This provides a road map for basic science and preclinical studies to identify key pathways in cancer and cells of the tumor microenvironment affected by these alterations, and candidate targets for new small molecule and biologic therapies.


          Recurrent chromosomal abnormalities, mutations, and expression of genes affecting HNSCC subsets are associated with differences in prognosis, and define molecules, pathways, and deregulated immune responses as candidates for therapy. Activity of molecularly targeted agents appears to be enhanced by rational combinations of these agents and standard therapies targeting the complex alterations that affect multiple pathways and mechanisms in HNSCC.

          Level of Evidence


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          Most cited references 48

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          Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

          Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
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            Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.

            The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we conducted comprehensive genomic analysis of gene expression, copy number, methylation, and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, and TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of caspase-8 (CASP8) defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating subset of head and neck cancers.
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              Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas.

              The genetic differences between human papilloma virus (HPV)-positive and -negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. To identify differential biology and novel therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC.

                Author and article information

                Laryngoscope Investig Otolaryngol
                Laryngoscope Investig Otolaryngol
                Laryngoscope Investigative Otolaryngology
                John Wiley and Sons Inc. (Hoboken )
                22 August 2017
                October 2017
                : 2
                : 5 ( doiID: 10.1002/lio2.v2.5 )
                : 310-319
                [ 1 ] Head and Neck Surgery Branch National Institute on Deafness and Other Communication Disorders Bethesda Maryland U.S.A
                Author notes
                [* ]Send correspondence to Carter Van Waes, MD, PhD, Building 10, Room 7N240D, 10 Center Drive, Bethesda, MD, USA, 20892. Email: vanwaesc@
                © 2017 The Authors Laryngoscope Investigative Otolaryngology published by Wiley Periodicals, Inc. on behalf of The Triological Society

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 1, Tables: 2, Pages: 10, Words: 7264
                Funded by: NIDCD Intramural Projects
                Award ID: ZIA-DC-000016
                Award ID: ZIA-DC-000073
                Award ID: ZIA-DC-000074
                Head and Neck, and Tumor Biology
                Head and Neck, and Tumor Biology
                Custom metadata
                October 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:25.10.2017


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