title: Transposon mutagenesis identifies genetic drivers of Braf(V600E) melanoma.
abstract: Although nearly half of human melanomas harbor oncogenic BRAF(V600E) mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in Braf(V600E) mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAF(V600E) melanoma and discover new genes with potential clinical importance in human melanoma.
authors.affiliation: 1] Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA. [2] Institute of Molecular and Cell Biology, Singapore.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Mann
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Black
authors.affiliation: Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Devin J
authors.initials: DJ
authors.lastname: Jones
authors.affiliation: Institute of Molecular and Cell Biology, Singapore.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: Institute of Molecular and Cell Biology, Singapore.
authors.forename: Christopher Chin Kuan
authors.initials: CC
authors.lastname: Yew
authors.affiliation: Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Justin Y
authors.initials: JY
authors.lastname: Newberg
authors.affiliation: Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.affiliation: 1] Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.affiliation: 1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA. [2] Department of Cell and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.affiliation: 1] Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand. [2] New Zealand Bioinformatics Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
authors.affiliation: 1] Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA. [2] Institute of Molecular and Cell Biology, Singapore.
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.affiliation: 1] Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA. [2] Institute of Molecular and Cell Biology, Singapore.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004251:DNA Transposable Elements / Q000235:genetics*; D059472:Exome; D005260:Female; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000556:secondary; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008868:Microtubule Proteins / Q000235:genetics*; D016296:Mutagenesis; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C509238:CEP350 protein, human; D004251:DNA Transposable Elements; D008868:Microtubule Proteins; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
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