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Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma

Nature Genetics volume 47, pages 486–495 (2015)Cite this article

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Abstract

Although nearly half of human melanomas harbor oncogenic BRAFV600E 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 BrafV600E 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 BRAFV600E melanoma and discover new genes with potential clinical importance in human melanoma.

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Figure 1: SB-mediated mutagenesis promotes melanoma formation in BrafV600E mutant mice.
Figure 2: Whole-exome sequencing of SB|Braf genomes.
Figure 3: Landscape of candidate driver genes mutated in SB|Braf melanoma.
Figure 4: Reduced netrin signaling in SB|Braf melanoma extends the phenotypic consequence of alterations in the Rho family of GTPases.
Figure 5: Significant clinical associations between SB|Braf CIS genes, RNA abundance and patient survival.
Figure 6: CEP350 is a melanoma tumor suppressor.

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Acknowledgements

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.

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Author notes

  1. Jerrold M Ward, Christopher Chin Kuan Yew & Alistair G Rust

    Present address: Present addresses: Global VetPathology, Montgomery Village, Maryland, USA (J.M.W.), National Heart Research Institute Singapore, Singapore (C.C.K.Y.) and Institute of Cancer Research, London, UK (A.G.R.).,

  2. Neal G Copeland and Nancy A Jenkins: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA

    Michael B Mann, Devin J Jones, Justin Y Newberg, Neal G Copeland & Nancy A Jenkins

  2. Institute of Molecular and Cell Biology, Singapore

    Michael B Mann, Jerrold M Ward, Christopher Chin Kuan Yew, Neal G Copeland & Nancy A Jenkins

  3. Department of Biochemistry, University of Otago, Dunedin, New Zealand

    Michael A Black

  4. Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA

    Adam J Dupuy

  5. Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK

    Alistair G Rust

  6. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA

    Marcus W Bosenberg

  7. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA

    Marcus W Bosenberg

  8. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.,

    Martin McMahon

  9. Department of Cell and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.,

    Martin McMahon

  10. Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

    Cristin G Print

  11. New Zealand Bioinformatics Institute, University of Auckland, Auckland, New Zealand

    Cristin G Print

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Contributions

M.B.M., N.G.C. and N.A.J. designed the study and wrote the manuscript. N.G.C. and N.A.J. directed the research. M.W.B. and M.M. provided essential biological resources and contributed to the experimental design. J.M.W. and M.W.B. performed histological classification and diagnosis of tumors. M.A.B., J.M.W., A.G.R., M.W.B., M.M. and C.G.P. contributed to editing of the manuscript before submission. M.B.M., M.A.B., D.J.J., J.M.W., C.C.K.Y., A.J.D., A.G.R. and C.G.P. performed data analysis. M.A.B., J.Y.N., A.J.D., A.G.R. and C.G.P. provided essential statistical and bioinformatics resources.

Corresponding author

Correspondence to Nancy A Jenkins.

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Mann, M., Black, M., Jones, D. et al. Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma. Nat Genet 47, 486–495 (2015). https://doi.org/10.1038/ng.3275

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  • DOI: https://doi.org/10.1038/ng.3275

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