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An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer

Author

Listed:
  • Rajdeep Das

    (University of California, San Francisco
    University of California, San Francisco)

  • Martin Sjöström

    (University of California, San Francisco
    University of California, San Francisco)

  • Raunak Shrestha

    (University of California, San Francisco
    University of California, San Francisco)

  • Christopher Yogodzinski

    (University of California, San Francisco
    University of California, San Francisco)

  • Emily A. Egusa

    (University of California, San Francisco
    University of California, San Francisco)

  • Lisa N. Chesner

    (University of California, San Francisco
    University of California, San Francisco)

  • William S. Chen

    (University of California, San Francisco
    University of California, San Francisco)

  • Jonathan Chou

    (University of California, San Francisco
    University of California, San Francisco)

  • Donna K. Dang

    (University of California, San Francisco
    University of California, San Francisco)

  • Jason T. Swinderman

    (University of California, San Francisco
    University of California, San Francisco)

  • Alex Ge

    (University of California, San Francisco
    University of California, San Francisco)

  • Junjie T. Hua

    (University of California, San Francisco
    University of California, San Francisco)

  • Shaheen Kabir

    (University of California, San Francisco
    University of California, San Francisco)

  • David A. Quigley

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Eric J. Small

    (University of California, San Francisco
    University of California, San Francisco)

  • Alan Ashworth

    (University of California, San Francisco
    University of California, San Francisco)

  • Felix Y. Feng

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Luke A. Gilbert

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

Abstract

Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.

Suggested Citation

  • Rajdeep Das & Martin Sjöström & Raunak Shrestha & Christopher Yogodzinski & Emily A. Egusa & Lisa N. Chesner & William S. Chen & Jonathan Chou & Donna K. Dang & Jason T. Swinderman & Alex Ge & Junjie , 2021. "An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24919-7
    DOI: 10.1038/s41467-021-24919-7
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