Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability

  1. Brenton R Paolella  Is a corresponding author
  2. William J Gibson
  3. Laura M Urbanski
  4. John A Alberta
  5. Travis I Zack
  6. Pratiti Bandopadhayay
  7. Caitlin A Nichols
  8. Pankaj K Agarwalla
  9. Meredith S Brown
  10. Rebecca Lamothe
  11. Yong Yu
  12. Peter S Choi
  13. Esther A Obeng
  14. Dirk Heckl
  15. Guo Wei
  16. Belinda Wang
  17. Aviad Tsherniak
  18. Francisca Vazquez
  19. Barbara A Weir
  20. David E Root
  21. Glenn S Cowley
  22. Sara J Buhrlage
  23. Charles D Stiles
  24. Benjamin L Ebert
  25. William C Hahn
  26. Robin Reed  Is a corresponding author
  27. Rameen Beroukhim  Is a corresponding author
  1. Dana-Farber Cancer Institute, Harvard Medical School, United States
  2. Harvard Medical School, United States
  3. Brigham and Women's Hospital, Harvard Medical School, United States
  4. Massachusetts Institute of Technology and Harvard University, United States

Abstract

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency.

Data availability

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Brenton R Paolella

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    For correspondence
    brenton_paolella@dfci.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3394-828X
  2. William J Gibson

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Laura M Urbanski

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. John A Alberta

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Travis I Zack

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Pratiti Bandopadhayay

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Caitlin A Nichols

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Pankaj K Agarwalla

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Meredith S Brown

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Rebecca Lamothe

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Yong Yu

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Peter S Choi

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Esther A Obeng

    Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Dirk Heckl

    Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Guo Wei

    Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Belinda Wang

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Aviad Tsherniak

    Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3797-1877
  18. Francisca Vazquez

    Broad Institute, Massachusetts Institute of Technology and Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Barbara A Weir

    Broad Institute, Massachusetts Institute of Technology and Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. David E Root

    Broad Institute, Massachusetts Institute of Technology and Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Glenn S Cowley

    Broad Institute, Massachusetts Institute of Technology and Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Sara J Buhrlage

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Charles D Stiles

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Benjamin L Ebert

    Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. William C Hahn

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2840-9791
  26. Robin Reed

    Department of Cell Biology, Harvard Medical School, Boston, United States
    For correspondence
    robin_reed@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  27. Rameen Beroukhim

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    For correspondence
    Rameen_Beroukhim@dfci.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Cancer Institute (F32 CA180653)

  • Brenton R Paolella

National Cancer Institute (P50 CA165962)

  • Charles D Stiles

The Sontag Foundation

  • Rameen Beroukhim

The Grey Matters Foundation

  • Rameen Beroukhim

The Pediatric Low Grade Astrocytoma Foundation

  • Pratiti Bandopadhayay
  • Charles D Stiles
  • Rameen Beroukhim

Friends for Life Fellowship

  • Brenton R Paolella

National Cancer Institute (R01 CA188228)

  • Rameen Beroukhim

National Cancer Institute (U01 CA176058)

  • William C Hahn

National Cancer Institute (F30 CA192725)

  • William J Gibson

National Institute of General Medical Sciences (R01 GM043375)

  • Robin Reed

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This work was conducted in accordance with and approved by the institutional animal care and use committee (IACUC) protocols (#15-014) of the Dana-Farber Cancer Institute.

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: November 14, 2016
  2. Accepted: February 6, 2017
  3. Accepted Manuscript published: February 8, 2017 (version 1)
  4. Version of Record published: March 17, 2017 (version 2)

Copyright

© 2017, Paolella et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Brenton R Paolella
  2. William J Gibson
  3. Laura M Urbanski
  4. John A Alberta
  5. Travis I Zack
  6. Pratiti Bandopadhayay
  7. Caitlin A Nichols
  8. Pankaj K Agarwalla
  9. Meredith S Brown
  10. Rebecca Lamothe
  11. Yong Yu
  12. Peter S Choi
  13. Esther A Obeng
  14. Dirk Heckl
  15. Guo Wei
  16. Belinda Wang
  17. Aviad Tsherniak
  18. Francisca Vazquez
  19. Barbara A Weir
  20. David E Root
  21. Glenn S Cowley
  22. Sara J Buhrlage
  23. Charles D Stiles
  24. Benjamin L Ebert
  25. William C Hahn
  26. Robin Reed
  27. Rameen Beroukhim
(2017)
Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
eLife 6:e23268.
https://doi.org/10.7554/eLife.23268

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