Mutational Landscape of Aggressive Cutaneous Squamous Cell Carcinoma

Curtis R. Pickering(The University of Texas MD Anderson Cancer Center), Jane H. Zhou(The University of Texas MD Anderson Cancer Center), J. Jack Lee(The University of Texas MD Anderson Cancer Center), Jennifer Drummond(Baylor College of Medicine), S. Andrew Peng(The University of Texas MD Anderson Cancer Center), Rami Saade(The University of Texas MD Anderson Cancer Center), Kenneth Y. Tsai(The University of Texas MD Anderson Cancer Center), Jonathan L. Curry(The University of Texas MD Anderson Cancer Center), Michael T. Tetzlaff(The University of Texas MD Anderson Cancer Center), Stephen Y. Lai(The University of Texas MD Anderson Cancer Center), Jun Yu(The University of Texas MD Anderson Cancer Center), Donna M. Muzny(Baylor College of Medicine), HarshaVardhan Doddapaneni(Baylor College of Medicine), Eve Shinbrot(Baylor College of Medicine), Kyle R. Covington(Baylor College of Medicine), Jianhua Zhang(The University of Texas MD Anderson Cancer Center), Sahil Seth(The University of Texas MD Anderson Cancer Center), Carlos Caulı́n(The University of Texas MD Anderson Cancer Center), Gary L. Clayman(The University of Texas MD Anderson Cancer Center), Adel K. El‐Naggar(The University of Texas MD Anderson Cancer Center), Richard A. Gibbs(Baylor College of Medicine), Randal S. Weber(The University of Texas MD Anderson Cancer Center), Jeffrey N. Myers(The University of Texas MD Anderson Cancer Center), David A. Wheeler(Baylor College of Medicine), Mitchell J. Frederick(The University of Texas MD Anderson Cancer Center)
Clinical Cancer Research
October 11, 2014
10.1158/1078-0432.ccr-14-1768
Cited by 606Open Access
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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.

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