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Science 333 (6046): 1154-1157

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

Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1

Nishant Agrawal,1,2,*,{dagger} Mitchell J. Frederick,3,* Curtis R. Pickering,3,* Chetan Bettegowda,2,4,* Kyle Chang,5 Ryan J. Li,1 Carole Fakhry,1 Tong-Xin Xie,3 Jiexin Zhang,6 Jing Wang,6 Nianxiang Zhang,6 Adel K. El-Naggar,7 Samar A. Jasser,3 John N. Weinstein,6 Lisa Treviño,5 Jennifer A. Drummond,5 Donna M. Muzny,5 Yuanqing Wu,5 Laura D. Wood,8 Ralph H. Hruban,8 William H. Westra,8 Wayne M. Koch,1 Joseph A. Califano,1,9 Richard A. Gibbs,5,9 David Sidransky,1 Bert Vogelstein,2 Victor E. Velculescu,2,{dagger} Nickolas Papadopoulos,2 David A. Wheeler,5 Kenneth W. Kinzler,2,{dagger} Jeffrey N. Myers3,{dagger}

Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

1 Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
2 Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
3 Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA.
4 Department of Neurosurgery, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
5 Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
6 Department of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA.
7 Department of Pathology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA.
8 Department of Pathology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
9 Milton J. Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.
10 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: nagrawal{at} (N.A.); velculescu{at} (V.E.V.); kinzlke{at} (K.W.K.); jmyers{at} (J.N.M.)

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