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Science 333 (6046): 1157-1160

Copyright © 2011 by the American Association for the Advancement of Science

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Nicolas Stransky,1,* Ann Marie Egloff,2,* Aaron D. Tward,1,3,4,* Aleksandar D. Kostic,1,5 Kristian Cibulskis,1 Andrey Sivachenko,1 Gregory V. Kryukov,1,5 Michael S. Lawrence,1 Carrie Sougnez,1 Aaron McKenna,1 Erica Shefler,1 Alex H. Ramos,1 Petar Stojanov,1 Scott L. Carter,1 Douglas Voet,1 Maria L. Cortés,1 Daniel Auclair,1 Michael F. Berger,1 Gordon Saksena,1 Candace Guiducci,1 Robert C. Onofrio,1 Melissa Parkin,1 Marjorie Romkes,6 Joel L. Weissfeld,7 Raja R. Seethala,8 Lin Wang,8 Claudia Rangel-Escareño,9 Juan Carlos Fernandez-Lopez,9 Alfredo Hidalgo-Miranda,9 Jorge Melendez-Zajgla,9 Wendy Winckler,1 Kristin Ardlie,1 Stacey B. Gabriel,1 Matthew Meyerson,1,5,10,11 Eric S. Lander,1,5,12 Gad Getz,1 Todd R. Golub,1,5,11,13,14,{dagger} Levi A. Garraway,1,5,10,11,{dagger},{ddagger} Jennifer R. Grandis2,15,{dagger},{ddagger}

Abstract: Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.

1 The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2 Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
3 Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02114, USA.
4 Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
5 Harvard Medical School, Boston, MA 02115, USA.
6 Department of Medicine, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA.
7 Department of Epidemiology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
8 Department of Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
9 Instituto Nacional de Medicina Genómica, Mexico City, 01900, Mexico.
10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
11 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
12 Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
13 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
14 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
15 Department of Pharmacology and Chemical Biology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: levi_garraway{at} (L.A.G.); grandisjr{at} (J.R.G.)

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Efficient methods for identifying mutated driver pathways in cancer.
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Bioinformatics 28, 2940-2947
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Genome Sequencing Identifies a Basis for Everolimus Sensitivity.
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Science 338, 221
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Comparative Genomic Analysis of Esophageal Adenocarcinoma and Squamous Cell Carcinoma.
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Chemopreventive and Chemotherapeutic Actions of mTOR Inhibitor in Genetically Defined Head and Neck Squamous Cell Carcinoma Mouse Model.
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