Editors' ChoiceCancer

The Downside of Diversity

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Science Signaling  30 Aug 2011:
Vol. 4, Issue 188, pp. ec241
DOI: 10.1126/scisignal.4188ec241

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. and Stransky et al. 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.

N. Agrawal, M. J. Frederick, C. R. Pickering, C. Bettegowda, K. Chang, R. J. Li, C. Fakhry, T.-X. Xie, J. Zhang, J. Wang, N. Zhang, A. K. El-Naggar, S. A. Jasser, J. N. Weinstein, L. Treviño, J. A. Drummond, D. M. Muzny, Y. Wu, L. D. Wood, R. H. Hruban, W. H. Westra, W. M. Koch, J. A. Califano, R. A. Gibbs, D. Sidransky, B. Vogelstein, V. E. Velculescu, N. Papadopoulos, D. A. Wheeler, K. W. Kinzler, J. N. Myers, Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333, 1154–1157 (2011). [Abstract] [Full Text]

N. Stransky, A. M. Egloff, A. D. Tward, A. D. Kostic, K. Cibulskis, A. Sivachenko, G. V. Kryukov, M. S. Lawrence, C. Sougnez, A. McKenna, E. Shefler, A. H. Ramos, P. Stojanov, S. L. Carter, D. Voet, M. L. Cortés, D. Auclair, M. F. Berger, G. Saksena, C. Guiducci, R. C. Onofrio, M. Parkin, M. Romkes, J. L. Weissfeld, R. R. Seethala, L. Wang, C. Rangel-Escareño, J. C. Fernandez-Lopez, A. Hidalgo-Miranda, J. Melendez-Zajgla, W. Winckler, K. Ardlie, S. B. Gabriel, M. Meyerson, E. S. Lander, G. Getz, T. R. Golub, L. A. Garraway, J. R. Grandis, The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011). [Abstract] [Full Text]

R. H. Brakenhoff, Another NOTCH for cancer. Science 333, 1102–1103 (2011). [Abstract] [Full Text]

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