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Clin Cancer Res. 2014 Dec 15;20(24):6582-92. doi: 10.1158/1078-0432.CCR-14-1768. Epub 2014 Oct 10.

Mutational landscape of aggressive cutaneous squamous cell carcinoma.

Author information

1
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
5
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Bioinformatics and Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
9
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. wheeler@bcm.edu mfrederi@mdanderson.org.
10
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. wheeler@bcm.edu mfrederi@mdanderson.org.

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.

PMID:
25303977
PMCID:
PMC4367811
DOI:
10.1158/1078-0432.CCR-14-1768
[Indexed for MEDLINE]
Free PMC Article

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