title: Use of clinical next-generation sequencing to identify melanomas harboring SMARCB1 mutations.
abstract: BACKGROUND
  SMARCB1 (INI1/BAF47/SNF5) encodes a part of a multiprotein complex that regulates gene expression through chromatin remodeling. SMARCB1 expression is lost or downregulated in multiple human tumors, including epithelioid sarcoma, meningioma and rhabdoid tumors of the brain, soft tissue and kidney.
  
  
  METHODS
  A 46-gene or 50-gene next-generation sequencing AmpliSeq Cancer Panel (Life Technologies; San Francisco, CA, USA) was applied to ∼1400 primary or metastatic melanoma tissues.
  
  
  RESULTS
  We identified eight cases of melanoma harboring mutations in SMARCB1. Immunohistochemistry demonstrated preservation of SMARCB1 protein expression in all cases. SMARCB1 mutations occurred together with TP53 mutations in five of the eight cases, suggesting a functional relationship between these tumor suppressors in melanoma.
  
  
  CONCLUSIONS
  Because single-base substitutions in SMARCB1 occur in a small subset of melanomas and do not affect SMARCB1 protein expression, such mutations would only be discovered by sequencing approaches. Our findings highlight the potential for next-generation sequencing platforms to identify mutations unexpected for melanoma that may contribute to its oncogenic potential. Though rare, the identification of SMARCB1 mutations adds to the growing literature regarding the role of epigenetic control mechanisms in melanoma progression and therapeutic resistance and provide a rationale for strategies targeting such alterations (via chromatin remodeling agents) in clinical trials.
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Stockman
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Curry
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Torres-Cabala
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Watson
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Siroy
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Roland L
authors.initials: RL
authors.lastname: Bassett
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts, Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Keyur P
authors.initials: KP
authors.lastname: Patel
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Routbort
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D000071796:SMARCB1 Protein; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
keywords: cancer research; malignant melanoma; molecular pathology