Transposon mutagenesis identifies genetic drivers of Braf V600E melanoma

Michael B. Mann; Michael A. Black; Devin J. Jones; Jerrold M. Ward; Christopher Chin Kuan Yew; Justin Y. Newberg; Adam J. Dupuy; Alistair G. Rust; Marcus W. Bosenberg; Martin Mcmahon; Cristin G. Print; Neal G. Copeland; Nancy A. Jenkins

doi:10.1038/ng.3275

Transposon mutagenesis identifies genetic drivers of Braf V600E melanoma

Michael B. Mann, Michael A. Black, Devin J. Jones, Jerrold M. Ward, Christopher Chin Kuan Yew, Justin Y. Newberg, Adam J. Dupuy, Alistair G. Rust, Marcus W. Bosenberg, Martin Mcmahon, Cristin G. Print, Neal G. Copeland, Nancy A. Jenkins

Weill Cornell Medical College

Research output: Contribution to journal › Article

39 Scopus citations

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.

Original language	English (US)
Pages (from-to)	486-495
Number of pages	10
Journal	Nature Genetics
Volume	47
Issue number	5
DOIs	https://doi.org/10.1038/ng.3275
State	Published - May 30 2015

ASJC Scopus subject areas

Genetics

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Transposon mutagenesis identifies genetic drivers of Braf V600E melanoma. / Mann, Michael B.; Black, Michael A.; Jones, Devin J.; Ward, Jerrold M.; Yew, Christopher Chin Kuan; Newberg, Justin Y.; Dupuy, Adam J.; Rust, Alistair G.; Bosenberg, Marcus W.; Mcmahon, Martin; Print, Cristin G.; Copeland, Neal G.; Jenkins, Nancy A.

In: Nature Genetics, Vol. 47, No. 5, 30.05.2015, p. 486-495.

Research output: Contribution to journal › Article

Mann, Michael B. ; Black, Michael A. ; Jones, Devin J. ; Ward, Jerrold M. ; Yew, Christopher Chin Kuan ; Newberg, Justin Y. ; Dupuy, Adam J. ; Rust, Alistair G. ; Bosenberg, Marcus W. ; Mcmahon, Martin ; Print, Cristin G. ; Copeland, Neal G. ; Jenkins, Nancy A. / Transposon mutagenesis identifies genetic drivers of Braf V600E melanoma. In: Nature Genetics. 2015 ; Vol. 47, No. 5. pp. 486-495.

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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.}",

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