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Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

Nature Genetics volume 44, pages 1006–1014 (2012)Cite this article

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Abstract

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

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Figure 1: Mutation spectrum in melanoma samples.
Figure 2: Schematic representation of PPP6C alterations.
Figure 3: Distribution of SCNAs and genes with high mutation loads in melanomas.
Figure 4: Crystal structure of RAC1P29S.
Figure 5: In vitro RAC1P29S binding to downstream effectors.
Figure 6: Cellular function of RAC1P29S compared to RAC1WT.

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Acknowledgements

This work was supported by the Yale SPORE in Skin Cancer funded by the National Cancer Institute grant number 1 P50 CA121974 (principal investigator, R.H.), the Melanoma Research Alliance (a Team award to R.H., M.B., M.K. and D.F.S.), The National Library of Medicine Training grant 5T15LM007056 (P.E.), the Department of Dermatology (R.H.), Yale Comprehensive Cancer Center (M.K.), the National Health and Medical Research Council of Australia (N.K.H. and K.D.-R.), Gilead Sciences, Inc. (J.S., M.K., R.H. and T.J.B.) and a generous gift from Roz and Jerry Meyer (R.H., M.S. and H.M.K.). We thank C. Truini, W. Meng, B. Speed, E. Straka, A. Raefski, M. Scallion and S. Levin for technical support, P. Parsons, C. Schmidt and colleagues at the Queensland Institute of Medical Research for generously providing many of the melanoma cell lines, the Yale Center for Genome Analysis and the Northeastern Collaborative Access Team (NE-CAT) facility at the Advanced Photon Source at Argonne National Laboratory.

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Authors and Affiliations

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

    Michael Krauthammer, Perry Evans, Jamie P McCusker, Ana Capatana & David F Stern

  2. Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA

    Yong Kong

  3. W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA

    Yong Kong

  4. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA

    Byung Hak Ha, Matthew J Davis, Joseph Schlessinger & Titus J Boggon

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

    Antonella Bacchiocchi, Elaine Cheng, Edna C Holman, Marcus Bosenberg, Douglas E Brash & Ruth Halaban

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

    Gerald Goh, Murim Choi, Douglas E Brash, Shrikant Mane, Kenneth K Kidd & Richard P Lifton

  7. Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Gerald Goh, Murim Choi & Richard P Lifton

  8. Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA

    Stephan Ariyan & Deepak Narayan

  9. Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia

    Ken Dutton-Regester

  10. Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    Ken Dutton-Regester & Nicholas K Hayward

  11. Comprehensive Cancer Center, Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USA

    Mario Sznol & Harriet M Kluger

  12. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Douglas E Brash

  13. Department of Ophthalmology, Yale University School of Medicine, New Haven, Connecticut, USA

    Miguel A Materin

  14. Department of Medicine, Division of Dermatology, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA

    Roger S Lo

  15. Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, Connecticut, USA

    Shrikant Mane

  16. Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut, USA

    Shrikant Mane

  17. School of Public Health, Yale University School of Medicine, New Haven, Connecticut, USA

    Shuangge Ma

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  1. Michael Krauthammer
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  29. Titus J Boggon
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  30. Ruth Halaban
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Contributions

M.K., R.H., R.P.L., J.S. and T.J.B. designed and supervised the study. Y.K., P.E., M.C., J.P.M., S. Ma, G.G. and A.C. performed the bioinformatic analyses. A.B., E.C., E.C.H., M.J.D., K.D.-R., K.K.K., N.K.H. and S. Mane collected and analyzed the melanoma samples and performed the sequencing and functional experiments. B.H.H. and T.J.B. performed the crystallographic studies. S.A., D.N., M.B., M.S., H.M.K., M.A.M. and R.S.L. provided the clinical specimens and the clinical annotation. D.E.B. and D.F.S. analyzed sun-related mutations. All authors contributed to the final version of the paper.

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Correspondence to Ruth Halaban.

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The authors declare no competing financial interests.

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Krauthammer, M., Kong, Y., Ha, B. et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44, 1006–1014 (2012). https://doi.org/10.1038/ng.2359

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