Title | Mutational landscape of aggressive cutaneous squamous cell carcinoma. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Pickering, CR, Zhou, JH, J Lee, J, Drummond, JA, S Peng, A, Saade, RE, Tsai, KY, Curry, JL, Tetzlaff, MT, Lai, SY, Yu, J, Muzny, DM, Doddapaneni, H, Shinbrot, E, Covington, KR, Zhang, J, Seth, S, Caulin, C, Clayman, GL, El-Naggar, AK, Gibbs, RA, Weber, RS, Myers, JN, Wheeler, DA, Frederick, MJ |
Journal | Clin Cancer Res |
Volume | 20 |
Issue | 24 |
Pagination | 6582-92 |
Date Published | 2014 Dec 15 |
ISSN | 1557-3265 |
Keywords | Carcinoma, Squamous Cell, Cluster Analysis, Computational Biology, Disease Progression, DNA Copy Number Variations, Exome, Genomics, High-Throughput Nucleotide Sequencing, Humans, Mutation, Prognosis, Skin Neoplasms |
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. |
DOI | 10.1158/1078-0432.CCR-14-1768 |
Alternate Journal | Clin Cancer Res |
PubMed ID | 25303977 |
PubMed Central ID | PMC4367811 |
Grant List | T32 CA163185 / CA / NCI NIH HHS / United States P30 CA016672 / CA / NCI NIH HHS / United States P50 CA097007 / CA / NCI NIH HHS / United States RC2DE020958 / DE / NIDCR NIH HHS / United States P30CA0CA16672 / CA / NCI NIH HHS / United States RC2 DE020958 / DE / NIDCR NIH HHS / United States T32CA163185 / CA / NCI NIH HHS / United States P50CA097007 / CA / NCI NIH HHS / United States |
Mutational landscape of aggressive cutaneous squamous cell carcinoma.
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