title: Mutational landscape of aggressive cutaneous squamous cell carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Pickering
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Zhou
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Drummond
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: S Andrew
authors.initials: SA
authors.lastname: Peng
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rami E
authors.initials: RE
authors.lastname: Saade
authors.affiliation: 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.
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Tsai
authors.affiliation: Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Curry
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Harshavardhan
authors.initials: H
authors.lastname: Doddapaneni
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Eve
authors.initials: E
authors.lastname: Shinbrot
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Department of Bioinformatics and Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sahil
authors.initials: S
authors.lastname: Seth
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caulin
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Clayman
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Randal S
authors.initials: RS
authors.lastname: Weber
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. wheeler@bcm.edu mfrederi@mdanderson.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. wheeler@bcm.edu mfrederi@mdanderson.org.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Frederick
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016000:Cluster Analysis; D019295:Computational Biology; D056915:DNA Copy Number Variations; D018450:Disease Progression; D059472:Exome; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D011379:Prognosis; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*