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Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

Author

Listed:
  • Michael Fraser

    (University of Toronto
    Princess Margaret Cancer Centre
    Ontario Institute for Cancer Research)

  • Julie Livingstone

    (University of California
    University of California
    University of California
    University of California)

  • Jeffrey L. Wrana

    (Mount Sinai Hospital
    Sinai Health System)

  • Antonio Finelli

    (University of Toronto
    Princess Margaret Cancer Centre
    Princess Margaret Cancer Centre)

  • Housheng Hansen He

    (Princess Margaret Cancer Centre
    University of Toronto)

  • Theodorus van der Kwast

    (University of Toronto
    University Health Network)

  • Alexandre R. Zlotta

    (University of Toronto
    Princess Margaret Cancer Centre
    Mount Sinai Hospital
    Sinai Health System)

  • Robert G. Bristow

    (University of Toronto
    Manchester Cancer Research Centre
    University of Manchester)

  • Paul C. Boutros

    (University of California
    University of California
    University of California
    University of California)

Abstract

Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.

Suggested Citation

  • Michael Fraser & Julie Livingstone & Jeffrey L. Wrana & Antonio Finelli & Housheng Hansen He & Theodorus van der Kwast & Alexandre R. Zlotta & Robert G. Bristow & Paul C. Boutros, 2021. "Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26489-0
    DOI: 10.1038/s41467-021-26489-0
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