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Recurrent inactivating RASA2 mutations in melanoma

Nature Genetics volume 47, pages 1408–1410 (2015)Cite this article

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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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Figure 1: Effects of RASA2 mutations on RAS activity, melanoma cell growth and patient survival.

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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.

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Authors and 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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  1. Rand Arafeh
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  2. Nouar Qutob
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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.

Corresponding author

Correspondence to Yardena Samuels.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Tables 4–8. (PDF 1259 kb)

Supplementary Table 1

Somatic mutations identified in 501 melanoma whole exomes and whole genomes. (XLSX 68530 kb)

Supplementary Table 2

Statistical calculation of significance of the somatic mutations identified in 499 melanoma whole exomes/genomes. (XLSX 522 kb)

Supplementary Table 3

Mutations identified in samples with RASA2 mutations. (XLSX 201151 kb)

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Arafeh, R., Qutob, N., Emmanuel, R. et al. Recurrent inactivating RASA2 mutations in melanoma. Nat Genet 47, 1408–1410 (2015). https://doi.org/10.1038/ng.3427

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