Journal article
Transposon mutagenesis identifies genetic drivers of Braf(V600E) melanoma
Nature genetics, Vol.47(5), pp.486-U86
05/2015
DOI: 10.1038/ng.3275
PMCID: PMC4844184
PMID: 25848750
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.
Details
- Title: Subtitle
- Transposon mutagenesis identifies genetic drivers of Braf(V600E) melanoma
- Creators
- Michael B Mann - 1] Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA. Institute of Molecular and Cell Biology, SingaporeMichael A Black - Department of Biochemistry, University of Otago, Dunedin, New ZealandDevin J Jones - Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USAJerrold M Ward - Institute of Molecular and Cell Biology, SingaporeChristopher Chin Kuan Yew - Institute of Molecular and Cell Biology, SingaporeJustin Y Newberg - Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USAAdam J Dupuy - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAAlistair G Rust - Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UKMarcus W Bosenberg - 1] Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USAMartin McMahon - 1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA. Department of Cell and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USACristin G Print - 1] Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand. New Zealand Bioinformatics Institute, University of Auckland, Auckland, New ZealandNeal G Copeland - 1] Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA. Institute of Molecular and Cell Biology, SingaporeNancy A Jenkins - 1] Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA. Institute of Molecular and Cell Biology, Singapore
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.47(5), pp.486-U86
- DOI
- 10.1038/ng.3275
- PMID
- 25848750
- PMCID
- PMC4844184
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Publisher
- Springer Science and Business Media LLC; United States
- Grant note
- P30 CA086862 / NCI NIH HHS R01 CA176839 / NCI NIH HHS
- Language
- English
- Date published
- 05/2015
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984025341002771
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