Mutational Landscape of Aggressive Cutaneous Squamous Cell Carcinoma

Clinical Cancer Research - Tập 20 Số 24 - Trang 6582-6592 - 2014
Curtis R. Pickering1, Jane H. Zhou2, J. Jack Lee3, Jennifer Drummond4, S. Andrew Peng3, Rami Saade1, Kenneth Y. Tsai5,6, Jonathan L. Curry5, Michael T. Tetzlaff2, Stephen Y. Lai1, Jun Yu3, Donna M. Muzny4, HarshaVardhan Doddapaneni4, Eve Shinbrot4, Kyle Covington4, Jianhua Zhang7, Sahil Seth7, Carlos Caulı́n1, Gary L. Clayman1, Adel K. El‐Naggar2, Richard A. Gibbs4,8, Randal S. Weber1, Jeffrey N. Myers1, David A. Wheeler4, Mitchell J. Frederick1
11Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
22Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
33Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
44Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
55Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
66Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
77Department of Bioinformatics and Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
88Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Tóm tắt

Abstract Purpose: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. Experimental Design: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. Results: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. Conclusions: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC. Clin Cancer Res; 20(24); 6582–92. ©2014 AACR.

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Clinical Cancer Research

Tập 20 Số 24

6582-6592

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