Mutational landscape of aggressive cutaneous squamous cell carcinoma.

TitleMutational landscape of aggressive cutaneous squamous cell carcinoma.
Publication TypeJournal Article
Year of Publication2014
AuthorsPickering, 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, HV, 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
JournalClin Cancer Res
Volume20
Issue24
Pagination6582-92
Date Published2014 Dec 15
ISSN1078-0432
KeywordsCarcinoma, 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.

DOI10.1158/1078-0432.CCR-14-1768
Alternate JournalClin. Cancer Res.
PubMed ID25303977
PubMed Central IDPMC4367811
Grant ListT32 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