Priority Research Papers:

The head and neck cancer cell oncogenome: A platform for the development of precision molecular therapies

Daniel Martin _, Martin C. Abba, Alfredo A. Molinolo, Lynn Vitale-Cross, Zhiyong Wang, Moraima Zaida, Naomi C. Delic, Yardena Samuels, Guy J. Lyons and J. Silvio Gutkind

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Oncotarget. 2014; 5:8906-8923. https://doi.org/10.18632/oncotarget.2417

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Daniel Martin1, Martin C. Abba2, Alfredo A. Molinolo1, Lynn Vitale-Cross1, Zhiyong Wang1, Moraima Zaida1, Naomi C. Delic4,5, Yardena Samuels3, J. Guy Lyons4,5, J. Silvio Gutkind1

1Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA

2CINIBA, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina

3Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel

4Dermatology, University of Sydney, Camperdown, Australia

5Cancer Services, Royal Prince Alfred Hospital, Camperdown, Australia

Correspondence to:

Silvio Gutkind, e-mail: [email protected]

Keywords: HNSCC, Sequencing, Exome, RNAseq, Cancer

Received: July 11, 2014     Accepted: August 28, 2014     Published: November 04, 2014


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.

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