The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Nicolas Stransky; Ann Marie Egloff; Aaron D. Tward; Aleksandar D. Kostic; Kristian Cibulskis; Andrey Sivachenko; Gregory V. Kryukov; Michael S. Lawrence; Carrie Sougnez; Aaron McKenna; Erica Shefler; Alex H. Ramos; Petar Stojanov; Scott L. Carter; Douglas Voet; Maria L. Cortés; Daniel Auclair; Michael F. Berger; Gordon Saksena; Candace Guiducci; Robert C. Onofrio; Melissa Parkin; Marjorie Romkes; Joel L. Weissfeld; Raja R. Seethala; Lin Wang; Claudia Rangel-Escareño; Juan Carlos Fernandez-Lopez; Alfredo Hidalgo-Miranda; Jorge Melendez-Zajgla; Wendy Winckler; Kristin Ardlie; Stacey B. Gabriel; Matthew Meyerson; Eric S. Lander; Gad Getz; Todd R. Golub; Levi A. Garraway; Jennifer R. Grandis

doi:10.1126/science.1208130

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The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Nicolas Stransky¹,*,
Ann Marie Egloff²,*,
Aaron D. Tward¹,³,⁴,*,
Aleksandar D. Kostic¹,⁵,
Kristian Cibulskis¹,
Andrey Sivachenko¹,
Gregory V. Kryukov¹,⁵,
Michael S. Lawrence¹,
Carrie Sougnez¹,
Aaron McKenna¹,
Erica Shefler¹,
Alex H. Ramos¹,
Petar Stojanov¹,
Scott L. Carter¹,
Douglas Voet¹,
Maria L. Cortés¹,
Daniel Auclair¹,
Michael F. Berger¹,
Gordon Saksena¹,
Candace Guiducci¹,
Robert C. Onofrio¹,
Melissa Parkin¹,
Marjorie Romkes⁶,
Joel L. Weissfeld⁷,
Raja R. Seethala⁸,
Lin Wang⁸,
Claudia Rangel-Escareño⁹,
Juan Carlos Fernandez-Lopez⁹,
Alfredo Hidalgo-Miranda⁹,
Jorge Melendez-Zajgla⁹,
Wendy Winckler¹,
Kristin Ardlie¹,
Stacey B. Gabriel¹,
Matthew Meyerson¹,⁵,¹⁰,¹¹,
Eric S. Lander¹,⁵,¹²,
Gad Getz¹,
Todd R. Golub¹,⁵,¹¹,¹³,¹⁴,†,
Levi A. Garraway¹,⁵,¹⁰,¹¹,†‡,
Jennifer R. Grandis²,¹⁵,†‡

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

↵‡To whom correspondence should be addressed. E-mail: levi_garraway{at}dfci.harvard.edu (L.A.G.); grandisjr{at}upmc.edu (J.R.G.)

↵* These authors contributed equally to this work.
↵† These authors contributed equally to this work.

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Science 26 Aug 2011:
Vol. 333, Issue 6046, pp. 1157-1160
DOI: 10.1126/science.1208130

Nicolas Stransky

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Ann Marie Egloff

2Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

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Aaron D. Tward

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

3Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02114, USA.

4Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

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Aleksandar D. Kostic

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

5Harvard Medical School, Boston, MA 02115, USA.

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Kristian Cibulskis

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Andrey Sivachenko

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Gregory V. Kryukov

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

5Harvard Medical School, Boston, MA 02115, USA.

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Michael S. Lawrence

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Carrie Sougnez

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Aaron McKenna

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Erica Shefler

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Alex H. Ramos

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Petar Stojanov

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Scott L. Carter

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Douglas Voet

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Maria L. Cortés

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Daniel Auclair

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Michael F. Berger

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Gordon Saksena

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Candace Guiducci

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Robert C. Onofrio

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Melissa Parkin

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Marjorie Romkes

6Department of Medicine, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA.

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Joel L. Weissfeld

7Department of Epidemiology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.

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Raja R. Seethala

8Department of Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

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Lin Wang

8Department of Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

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Claudia Rangel-Escareño

9Instituto Nacional de Medicina Genómica, Mexico City, 01900, Mexico.

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Juan Carlos Fernandez-Lopez

9Instituto Nacional de Medicina Genómica, Mexico City, 01900, Mexico.

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Alfredo Hidalgo-Miranda

9Instituto Nacional de Medicina Genómica, Mexico City, 01900, Mexico.

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Jorge Melendez-Zajgla

9Instituto Nacional de Medicina Genómica, Mexico City, 01900, Mexico.

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Wendy Winckler

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Kristin Ardlie

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Stacey B. Gabriel

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Matthew Meyerson

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

5Harvard Medical School, Boston, MA 02115, USA.

10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

11Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

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Eric S. Lander

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

5Harvard Medical School, Boston, MA 02115, USA.

12Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

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Gad Getz

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Todd R. Golub

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

5Harvard Medical School, Boston, MA 02115, USA.

11Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

13Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

14Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

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Levi A. Garraway

1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

5Harvard Medical School, Boston, MA 02115, USA.

10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

11Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

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For correspondence: levi_garraway@dfci.harvard.edu grandisjr@upmc.edu

Jennifer R. Grandis

2Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

15Department of Pharmacology and Chemical Biology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

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For correspondence: levi_garraway@dfci.harvard.edu grandisjr@upmc.edu

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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.

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The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

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