@article{25db96394dd94f4784715988945bdb15,
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.",
author = "Mann, {Michael B.} and Black, {Michael A.} and Jones, {Devin J.} and Ward, {Jerrold M.} and Yew, {Christopher Chin Kuan} and Newberg, {Justin Y.} and Dupuy, {Adam J.} and Rust, {Alistair G.} and Bosenberg, {Marcus W.} and Martin Mcmahon and Print, {Cristin G.} and Copeland, {Neal G.} and Jenkins, {Nancy A.}",
note = "Funding Information: The authors thank K. Mann for helpful discussions and for critical reading and editing of the manuscript; M. Eccles (Otago) and the Copeland and Jenkins laboratories in Singapore and Houston for helpful discussions; V. Hearing (National Cancer Institute) for PEP antibodies and L. Chin (Dana-Farber Cancer Institute) for Tyr-creERT2 mice; D. Adams (Sanger Institute), T. Whipp, R. Rance and the Wellcome Trust Sanger Institute sequencing and informatics teams for 454 sequencing and bioinformatics support; K. Rogers, S. Rogers and the Institute for Molecular and Cell Biology Histopathology Core; P. Cheok, N. Lim, D. Chen and C. Wee (Singapore) and H. Lee and E. Freiter (Houston) for assistance with tumor monitoring and animal husbandry; and A. Trevarton (Auckland) for assistance with molecular pathway analysis. Histology work was performed by the Advanced Molecular Pathology Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore. This work was supported in part by the Biomedical Research Council, A*STAR, Singapore (to N.G.C. and N.A.J.), the Cancer Prevention Research Institute of Texas (to N.G.C. and N.A.J.), the Health Research Council of New Zealand, the University of Auckland and the New Zealand Maurice Wilkins Centre (to C.G.P.), the National Cancer Institute (to M.M. and M.W.B.) and the Melanoma Research Alliance (to M.M.). N.G.C. and N.A.J. are also Cancer Prevention Research Institute of Texas Scholars in Cancer Research. Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2015",
month = may,
day = "30",
doi = "10.1038/ng.3275",
language = "English (US)",
volume = "47",
pages = "486--495",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "5",
}