Abstract

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample–specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

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Acknowledgements

We thank F. Schütz and P. Bady for statistical discussions, P. Descombes for high-throughput sequencing, D. Martinet for aCGH data and C. Rivolta for valuable comments on the manuscript. We thank A. Simpson and R. Strausberg for their constant support. Part of the computation was performed on the cluster at the Vital-IT computing center. This work was supported by the Ludwig Institute for Cancer Research (C.I. and S.E.A.), the Hilton-Ludwig Cancer Metastasis Initiative, funded by the Conrad N. Hilton Foundation (D.R.), the Swiss National Science Foundation (SNF) National Centres of Competence in Research (NCCR) Frontiers in Genetics (S.E.A.) and the European Research Council (ERC; S.E.A.).

Author information

Author notes

    • Sergey I Nikolaev
    • , Donata Rimoldi
    •  & Christian Iseli

    These authors contributed equally to this work.

Affiliations

  1. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.

    • Sergey I Nikolaev
    • , Daniel Robyr
    • , Corinne Gehrig
    • , Michel Guipponi
    •  & Stylianos E Antonarakis
  2. Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.

    • Donata Rimoldi
    • , Christian Iseli
    • , Armand Valsesia
    • , Olivier Michielin
    • , Katja Muehlethaler
    • , Daniel Speiser
    • , C Victor Jongeneel
    •  & Brian J Stevenson
  3. Swiss Institute of Bioinformatics, Lausanne, Switzerland.

    • Christian Iseli
    • , Armand Valsesia
    • , Vincent Zoete
    • , Olivier Michielin
    • , Ioannis Xenarios
    • , C Victor Jongeneel
    •  & Brian J Stevenson
  4. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Armand Valsesia
    •  & Jacques S Beckmann
  5. Lausanne Genomic Technologies Facility, Center for Integrative Genomics, Lausanne, Switzerland.

    • Keith Harshman
  6. Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.

    • Olesya Bukach
  7. Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

    • Olivier Michielin
  8. Service of Medical Genetics, CHUV, Lausanne, Switzerland.

    • Jacques S Beckmann
  9. Department of Molecular Biology, University of Geneva, Geneva, Switzerland.

    • Thanos D Halazonetis
  10. National Center for Supercomputing Applications, University of Illinois, Urbana, Illinois, USA.

    • C Victor Jongeneel
  11. Institute for Genomic Biology, University of Illinois, Urbana, Illinois, USA.

    • C Victor Jongeneel
  12. Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.

    • Stylianos E Antonarakis

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Contributions

S.I.N., C.I., A.V., D. Rimoldi, B.J.S., C.V.J., J.S.B., T.D.H. and S.E.A. designed experiments and wrote the manuscript. A.V., B.J.S. and C.I. performed statistical analysis. D. Rimoldi and K.M. established cell lines, prepared samples and performed functional studies. S.I.N., C.G., M.G. and K.H. performed exome sequencing and validations. S.I.N., C.I., A.V., B.J.S., D. Robyr, D. Rimoldi O.B., I.X. and S.E.A. analyzed the results. V.Z. and O.M. performed in silico modeling. D.S. and O.M. procured subject material. All authors commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sergey I Nikolaev or Donata Rimoldi or Stylianos E Antonarakis.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–10 and Supplementary Tables 2, 3 and 5–8.

Excel files

  1. 1.

    Supplementary Table 1

    List of all somatic mutations in the studied melanomas (Excel)

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    Supplementary Table 4

    Copy number of genes from aCGH and SNP arrays and transcript expression (Excel)

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DOI

https://doi.org/10.1038/ng.1026

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