Published online 28 July 2011
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 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 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, and Jennifer R. Grandis
施設はHarvard Medical SchoolとUniversity of Pittsburgh等々
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.
Published online 28 July 2011
Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1
Nishant Agrawal, Mitchell J. Frederick, Curtis R. Pickering, Chetan Bettegowda, Kyle Chang, Ryan J. Li, Carole Fakhry, Tong-Xin Xie, Jiexin Zhang, Jing Wang, Nianxiang Zhang, Adel K. El-Naggar, Samar A. Jasser, John N. Weinstein, Lisa Treviño, Jennifer A. Drummond, Donna M. Muzny, Yuanqing Wu, Laura D. Wood, Ralph H. Hruban, William H. Westra, Wayne M. Koch, Joseph A. Califano, Richard A. Gibbs, David Sidransky, Bert Vogelstein, Victor E. Velculescu, Nickolas Papadopoulos, David A. Wheeler, Kenneth W. Kinzler, and Jeffrey N. Myers
施設はJohns Hopkins Universityが主
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 papilloma virus (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. Interestingly, 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.