Abstract

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes.

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Acknowledgements

This project was supported in part by US National Institutes of Health grants R01 CA154480, R01 CA121941, U01 CA176058, R01 CA109467 and U01 CA184898-02.

Author information

Author notes

    • Jong Wook Kim
    •  & Olga B Botvinnik

    These authors contributed equally to this work.

Affiliations

  1. Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Jong Wook Kim
    • , Olga B Botvinnik
    • , Omar Abudayyeh
    • , Chet Birger
    • , Joseph Rosenbluh
    • , Yashaswi Shrestha
    • , Mohamed E Abazeed
    • , Peter S Hammerman
    • , Daniel DiCara
    • , David J Konieczkowski
    • , Cory M Johannessen
    • , Arthur Liberzon
    • , Gabriela Alexe
    • , Andrew Aguirre
    • , Mahmoud Ghandi
    • , Heidi Greulich
    • , Francisca Vazquez
    • , Barbara A Weir
    • , Eliezer M Van Allen
    • , Aviad Tsherniak
    • , Diane D Shao
    • , Travis I Zack
    • , Michael Noble
    • , Gad Getz
    • , Rameen Beroukhim
    • , Levi A Garraway
    • , David A Barbie
    • , Jesse S Boehm
    • , William C Hahn
    • , Jill P Mesirov
    •  & Pablo Tamayo
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Jong Wook Kim
    • , Omar Abudayyeh
    • , Joseph Rosenbluh
    • , Yashaswi Shrestha
    • , David J Konieczkowski
    • , Cory M Johannessen
    • , Andrew Aguirre
    • , Heidi Greulich
    • , Francisca Vazquez
    • , Eliezer M Van Allen
    • , Diane D Shao
    • , Rameen Beroukhim
    • , Levi A Garraway
    • , David A Barbie
    •  & William C Hahn
  3. Bioinformatics and Systems Biology Program, University of California at San Diego, La Jolla, California, USA.

    • Olga B Botvinnik
  4. Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA.

    • Olga B Botvinnik
  5. Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA.

    • Olga B Botvinnik
  6. Harvard Medical School, Boston, Massachusetts, USA.

    • Omar Abudayyeh
    •  & Peter S Hammerman
  7. Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA.

    • Mohamed E Abazeed
  8. Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

    • Peter S Hammerman
  9. Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada.

    • Amir Reza Alizad-Rahvar
    •  & Masoud Ardakani
  10. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Gabriela Alexe
  11. Boston Children's Hospital, Boston, Massachusetts, USA.

    • Gabriela Alexe
  12. Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA.

    • Gabriela Alexe
  13. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Heidi Greulich
    • , Rameen Beroukhim
    • , Levi A Garraway
    •  & William C Hahn
  14. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Travis I Zack
  15. Program in Biophysics, Harvard University, Boston, Massachusetts, USA.

    • Travis I Zack
    •  & Rameen Beroukhim
  16. Department of Biology, University of Padova, Padova, Italy.

    • Chiara Romualdi
    •  & Gabriele Sales
  17. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • William C Hahn
  18. Department of Medicine, University of California San Diego, La Jolla, California, USA.

    • Jill P Mesirov
    •  & Pablo Tamayo
  19. Moores Cancer Center, University of California San Diego, La Jolla, California, USA.

    • Jill P Mesirov
    •  & Pablo Tamayo

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Contributions

J.W.K., O.B.B., J.P.M., J.S.B., W.C.H. and P.T. designed and conceptualized the method. O.B.B., O.A., C.B. and P.T. implemented the algorithm. J.W.K., D.A.B., J.R., Y.S., M.E.A., P.S.H., A.A., H.G., F.V., B.A.W., E.M.V.A., D.D.S., T.I.Z., R.B., L.A.G., C.M.J., D.J.K, J.P.M. and P.T. analyzed and interpreted results. A.R.A.-R., M.A., C.R., G.S., D.D., G.G., M.G., G.A., M.N., A.L., A.T. and P.T. provided expertise or work on specific issues regarding algorithmic approaches, data analysis, data preparation, data resources, benchmarking, validation datasets and method comparisons. J.W.K., O.B.B., M.E.A., J.R., J.P.M. and P.T. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pablo Tamayo.

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DOI

https://doi.org/10.1038/nbt.3527

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