The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

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 papillomavi...

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Published in	Science (American Association for the Advancement of Science) Vol. 333; no. 6046; pp. 1157 - 1160
Main Authors	Stransky, Nicolas, Egloff, Ann Marie, Tward, Aaron D., Kostic, Aleksandar D., Cibulskis, Kristian, Sivachenko, Andrey, Kryukov, Gregory V., Lawrence, Michael S., Sougnez, Carrie, McKenna, Aaron, Shefler, Erica, Ramos, Alex H., Stojanov, Petar, Carter, Scott L., Voet, Douglas, Cortés, Maria L., Auclair, Daniel, Berger, Michael F., Saksena, Gordon, Guiducci, Candace, Onofrio, Robert C., Parkin, Melissa, Romkes, Marjorie, Weissfeld, Joel L., Seethala, Raja R., Wang, Lin, Rangel-Escareño, Claudia, Fernandez-Lopez, Juan Carlos, Hidalgo-Miranda, Alfredo, Melendez-Zajgla, Jorge, Winckler, Wendy, Ardlie, Kristin, Gabriel, Stacey B., Meyerson, Matthew, Lander, Eric S., Getz, Gad, Golub, Todd R., Garraway, Levi A., Grandis, Jennifer R.
Format	Journal Article
Language	English
Published	Washington, DC American Association for the Advancement of Science 26.08.2011 The American Association for the Advancement of Science
Subjects	Algorithms Apoptosis Biological and medical sciences Cancer Carcinogenesis Carcinoma - genetics Carcinoma - metabolism Carcinoma - virology Carcinoma, Squamous Cell Cell Differentiation Coding DNA Environmental factors Environmental Influences Epidemiology Etiology Exons Genes Genetic mutation Genetics Genomes Head Head & neck cancer Head and Neck Neoplasms - genetics Head and Neck Neoplasms - metabolism Head and Neck Neoplasms - virology Human papillomavirus Humans Independent Study Individualized Instruction Medical sciences Mutation Neck Neoplasms, Squamous Cell - genetics Neoplasms, Squamous Cell - metabolism Neoplasms, Squamous Cell - virology Otorhinolaryngology (head neck, general aspects and miscellaneous) Otorhinolaryngology. Stomatology Papillomaviridae Papillomaviridae - isolation & purification Papillomavirus Infections - virology Point Mutation Receptor, Notch1 - genetics Receptor, Notch1 - metabolism Risk factors Sequence Analysis, DNA Sequence Deletion Sequencing Signal Transduction Smoking Squamous cell carcinoma Squamous Cell Carcinoma of Head and Neck Tobacco Tobacco Products Tumors Human TP63 gene Tobacco smoking Papovaviridae Malignant tumor Carcinogenesis Infection Papillomavirus Virus Human papillomavirus Cancerology Viral disease Exome sequencing Genetics ENT disease Head and neck cancer Head and neck squamous cell carcinoma Mutation Interferon regulatory factor Cancer Tumor suppressor gene
Online Access	Get full text
ISSN	0036-8075 1095-9203 1095-9203
DOI	10.1126/science.1208130

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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.
AbstractList	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. Head and neck squamous cell carcinoma (HNSCC) affects about 600,000 individuals each year and has a mortality rate of about 50%. Environmental factors such as tobacco and alcohol use and human papillomavirus (HPV) infection are key participants in pathogenesis (see the Perspective by Brakenhoff). In independent studies aimed at exploring the molecular genetics of these tumors, Agrawal et al. (p. 1154, published online 28 July) and Stransky et al. (p. 1157, published online 28 July) sequenced the protein-coding genes of multiple tumors. Tumors from smokers had more mutations than those from nonsmokers, and tumors that were HPV-positive had fewer mutations than HPV-negative tumors. HNSCCs harbored mutations in a diverse array of genes, including genes implicated in squamous differentiation such as NOTCH1. Notably, the pattern of NOTCH1 mutations suggests that this gene acts as a tumor suppressor in HNSCC, in direct contrast to its role as an oncogene in other tumor types. The diverse mutational etiology of HNSCC and the dearth of activating mutations in established oncogenes suggest that targeted therapies for the disease will be especially challenging, which emphasizes the importance of prevention and early detection. 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. [PUBLICATION ABSTRACT] The mutational profile of head and neck cancer is complex and may pose challenges to the development of targeted therapies. 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. 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.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. 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 papilloma virus was detectable by sequencing of DNA from infected tumors. In addition to identifying previously known HNSCC genes ( TP53 , CDKN2A , PTEN , PIK3CA , and HRAS ), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (e.g., 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.
Author	Kryukov, Gregory V. Sougnez, Carrie Weissfeld, Joel L. Rangel-Escareño, Claudia Tward, Aaron D. Golub, Todd R. Shefler, Erica Winckler, Wendy Fernandez-Lopez, Juan Carlos McKenna, Aaron Ramos, Alex H. Parkin, Melissa Carter, Scott L. Romkes, Marjorie Egloff, Ann Marie Auclair, Daniel Sivachenko, Andrey Kostic, Aleksandar D. Guiducci, Candace Lawrence, Michael S. Saksena, Gordon Cortés, Maria L. Lander, Eric S. Seethala, Raja R. Onofrio, Robert C. Cibulskis, Kristian Voet, Douglas Hidalgo-Miranda, Alfredo Meyerson, Matthew Stransky, Nicolas Grandis, Jennifer R. Melendez-Zajgla, Jorge Garraway, Levi A. Gabriel, Stacey B. Wang, Lin Berger, Michael F. Ardlie, Kristin Getz, Gad Stojanov, Petar
AuthorAffiliation	5 Harvard Medical School, Boston, MA 02115, USA 14 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA 1 The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 15 Department of Pharmacology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA 12 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA 6 Department of Medicine, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA 11 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA 7 Department of Epidemiology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA 9 Instituto Nacional de Medicina Genómica, Mexico City, 01900, Mexico 3 Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02114, USA 2 Department of Otolaryn
AuthorAffiliation_xml	– name: 12 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA – name: 7 Department of Epidemiology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA – name: 8 Department of Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA – name: 4 Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA – name: 13 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA – name: 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA – name: 6 Department of Medicine, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA – name: 14 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA – name: 3 Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02114, USA – name: 11 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA – name: 2 Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA – name: 1 The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – name: 9 Instituto Nacional de Medicina Genómica, Mexico City, 01900, Mexico – name: 5 Harvard Medical School, Boston, MA 02115, USA – name: 15 Department of Pharmacology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
Author_xml	– sequence: 1 givenname: Nicolas surname: Stransky fullname: Stransky, Nicolas – sequence: 2 givenname: Ann Marie surname: Egloff fullname: Egloff, Ann Marie – sequence: 3 givenname: Aaron D. surname: Tward fullname: Tward, Aaron D. – sequence: 4 givenname: Aleksandar D. surname: Kostic fullname: Kostic, Aleksandar D. – sequence: 5 givenname: Kristian surname: Cibulskis fullname: Cibulskis, Kristian – sequence: 6 givenname: Andrey surname: Sivachenko fullname: Sivachenko, Andrey – sequence: 7 givenname: Gregory V. surname: Kryukov fullname: Kryukov, Gregory V. – sequence: 8 givenname: Michael S. surname: Lawrence fullname: Lawrence, Michael S. – sequence: 9 givenname: Carrie surname: Sougnez fullname: Sougnez, Carrie – sequence: 10 givenname: Aaron surname: McKenna fullname: McKenna, Aaron – sequence: 11 givenname: Erica surname: Shefler fullname: Shefler, Erica – sequence: 12 givenname: Alex H. surname: Ramos fullname: Ramos, Alex H. – sequence: 13 givenname: Petar surname: Stojanov fullname: Stojanov, Petar – sequence: 14 givenname: Scott L. surname: Carter fullname: Carter, Scott L. – sequence: 15 givenname: Douglas surname: Voet fullname: Voet, Douglas – sequence: 16 givenname: Maria L. surname: Cortés fullname: Cortés, Maria L. – sequence: 17 givenname: Daniel surname: Auclair fullname: Auclair, Daniel – sequence: 18 givenname: Michael F. surname: Berger fullname: Berger, Michael F. – sequence: 19 givenname: Gordon surname: Saksena fullname: Saksena, Gordon – sequence: 20 givenname: Candace surname: Guiducci fullname: Guiducci, Candace – sequence: 21 givenname: Robert C. surname: Onofrio fullname: Onofrio, Robert C. – sequence: 22 givenname: Melissa surname: Parkin fullname: Parkin, Melissa – sequence: 23 givenname: Marjorie surname: Romkes fullname: Romkes, Marjorie – sequence: 24 givenname: Joel L. surname: Weissfeld fullname: Weissfeld, Joel L. – sequence: 25 givenname: Raja R. surname: Seethala fullname: Seethala, Raja R. – sequence: 26 givenname: Lin surname: Wang fullname: Wang, Lin – sequence: 27 givenname: Claudia surname: Rangel-Escareño fullname: Rangel-Escareño, Claudia – sequence: 28 givenname: Juan Carlos surname: Fernandez-Lopez fullname: Fernandez-Lopez, Juan Carlos – sequence: 29 givenname: Alfredo surname: Hidalgo-Miranda fullname: Hidalgo-Miranda, Alfredo – sequence: 30 givenname: Jorge surname: Melendez-Zajgla fullname: Melendez-Zajgla, Jorge – sequence: 31 givenname: Wendy surname: Winckler fullname: Winckler, Wendy – sequence: 32 givenname: Kristin surname: Ardlie fullname: Ardlie, Kristin – sequence: 33 givenname: Stacey B. surname: Gabriel fullname: Gabriel, Stacey B. – sequence: 34 givenname: Matthew surname: Meyerson fullname: Meyerson, Matthew – sequence: 35 givenname: Eric S. surname: Lander fullname: Lander, Eric S. – sequence: 36 givenname: Gad surname: Getz fullname: Getz, Gad – sequence: 37 givenname: Todd R. surname: Golub fullname: Golub, Todd R. – sequence: 38 givenname: Levi A. surname: Garraway fullname: Garraway, Levi A. – sequence: 39 givenname: Jennifer R. surname: Grandis fullname: Grandis, Jennifer R.
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Keywords	Human TP63 gene Tobacco smoking Papovaviridae Malignant tumor Carcinogenesis Infection Papillomavirus Virus Human papillomavirus Cancerology Viral disease Exome sequencing Genetics ENT disease Head and neck cancer Head and neck squamous cell carcinoma Mutation Interferon regulatory factor Cancer Tumor suppressor gene
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Snippet	Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed... The mutational profile of head and neck cancer is complex and may pose challenges to the development of targeted therapies. Head and neck squamous cell... Head and neck squamous cell carcinoma (HNSCC) affects about 600,000 individuals each year and has a mortality rate of about 50%. Environmental factors such as...
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SubjectTerms	Algorithms Apoptosis Biological and medical sciences Cancer Carcinogenesis Carcinoma - genetics Carcinoma - metabolism Carcinoma - virology Carcinoma, Squamous Cell Cell Differentiation Coding DNA Environmental factors Environmental Influences Epidemiology Etiology Exons Genes Genetic mutation Genetics Genomes Head Head & neck cancer Head and Neck Neoplasms - genetics Head and Neck Neoplasms - metabolism Head and Neck Neoplasms - virology Human papillomavirus Humans Independent Study Individualized Instruction Medical sciences Mutation Neck Neoplasms, Squamous Cell - genetics Neoplasms, Squamous Cell - metabolism Neoplasms, Squamous Cell - virology Otorhinolaryngology (head neck, general aspects and miscellaneous) Otorhinolaryngology. Stomatology Papillomaviridae Papillomaviridae - isolation & purification Papillomavirus Infections - virology Point Mutation Receptor, Notch1 - genetics Receptor, Notch1 - metabolism Risk factors Sequence Analysis, DNA Sequence Deletion Sequencing Signal Transduction Smoking Squamous cell carcinoma Squamous Cell Carcinoma of Head and Neck Tobacco Tobacco Products Tumors
Title	The Mutational Landscape of Head and Neck Squamous Cell Carcinoma
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