title: The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies.
abstract: The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53, FAT1, CDK2NA, CASP8, and NOTCH1, and copy number variations (CNVs) and mutations in PIK3CA, HRAS, and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV+ HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV+ HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.affiliation: CINIBA, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Abba
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Vitale-Cross
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA.
authors.forename: Moraima
authors.initials: M
authors.lastname: Zaida
authors.affiliation: Dermatology, University of Sydney, Camperdown, Australia. Cancer Services, Royal Prince Alfred Hospital, Camperdown, Australia.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Delic
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
authors.affiliation: Dermatology, University of Sydney, Camperdown, Australia. Cancer Services, Royal Prince Alfred Hospital, Camperdown, Australia.
authors.forename: J Guy
authors.initials: JG
authors.lastname: Lyons
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D001483:Base Sequence; D015820:Cadherins / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D057285:Precision Medicine; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D017422:Sequence Analysis, DNA; D051901:Smad4 Protein / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D015820:Cadherins; D053181:Caspase 8; D058534:Class I Phosphatidylinositol 3-Kinases; D051357:Cyclin-Dependent Kinase 2; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras); D051881:Receptor, Notch1; D051901:Smad4 Protein; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C502403:FAT1 protein, human; C497761:NOTCH1 protein, human; C497796:SMAD4 protein, human; C495901:TP53 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C495894:CDK2 protein, human; C494929:PTEN protein, human; C505530:CASP8 protein, human; C501009:HRAS protein, human