Abstract

Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer.

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Acknowledgements

We thank T. Wiesel for graphical assistance. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Cancer Institute, as well as by program grants of the Australian National Health and Medical Research Council (NHMRC) and Cancer Institute NSW. Y.S. is supported by the Israel Science Foundation through grants 1604/13 and 877/13, the European Research Council (ERC; StG-335377), the ERC under the European Union's Horizon 2020 research and innovation program (grant agreement 677645), the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the estate of Alice Schwarz-Gardos, the estate of John Hunter, the Knell Family, the Peter and Patricia Gruber Award and the Hamburger Family. I.U. is supported by a grant from the Rising Tide Foundation. N.K.H., K.D.-R. and R.A.S. are supported by fellowships from the NHMRC. A.L.P. is supported by Cure Cancer Australia. Support from the Melanoma Institute Australia is also gratefully acknowledged. We thank the TCGA Research Network for generating some of the data sets.

Author information

Affiliations

  1. Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, Israel.

    • Rand Arafeh
    • , Nouar Qutob
    • , Rafi Emmanuel
    • , Alona Keren-Paz
    • , Sabina Winograd-Katz
    • , Yael Hevroni
    •  & Yardena Samuels
  2. Melanoma Institute Australia, Sydney, New South Wales, Australia.

    • Jason Madore
    • , James S Wilmott
    • , Graham J Mann
    •  & Richard A Scolyer
  3. Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.

    • Jason Madore
    • , James S Wilmott
    • , Graham J Mann
    •  & Richard A Scolyer
  4. National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Abdel Elkahloun
    •  & Victoria K Hill
  5. National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Jared J Gartner
    • , Sivasish Sindiri
    • , Jimmy C Lin
    • , Steven A Rosenberg
    •  & Javed Khan
  6. Institute of Biochemistry, Food Science and Nutrition, Hebrew University, Rehovot, Israel.

    • Antonella Di Pizio
    •  & Masha Y Niv
  7. Department of Biological Services, Weizmann Institute of Science, Rehovot, Israel.

    • Ron Rotkopf
    •  & Shifra Ben-Dor
  8. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Ken Dutton-Regester
    • , Peter Johansson
    • , Antonia L Pritchard
    • , Nicola Waddell
    •  & Nicholas K Hayward
  9. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.

    • Igor Ulitsky
  10. Centre for Cancer Research, Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.

    • Graham J Mann
  11. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

    • Richard A Scolyer

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Contributions

R.A., N.Q., R.E., A.K.-P., J.J.G. and Y.S. designed the study. J.M., A.E., J.S.W., J.J.G., K.D.-R., P.J., A.L.P., N.W., G.J.M., R.A.S., N.K.H. and S.A.R. collected and analyzed the melanoma samples. S.S., R.R., J.C.L., J.K., S.B.-D. and I.U. analyzed the genetic data. R.A., R.E., S.W.-K., V.K.H., Y.H. and J.M. performed the functional experiments and analyzed the data. A.D.P. and M.Y.N. performed the structural analysis. All authors contributed to the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yardena Samuels.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–9 and Supplementary Tables 4–8.

Excel files

  1. 1.

    Supplementary Table 1

    Somatic mutations identified in 501 melanoma whole exomes and whole genomes.

  2. 2.

    Supplementary Table 2

    Statistical calculation of significance of the somatic mutations identified in 499 melanoma whole exomes/genomes.

  3. 3.

    Supplementary Table 3

    Mutations identified in samples with RASA2 mutations.

About this article

Publication history

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Accepted

Published

DOI

https://doi.org/10.1038/ng.3427

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