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

Michael Fraser (), Julie Livingstone, Jeffrey L. Wrana, Antonio Finelli, Housheng Hansen He, Theodorus van der Kwast, Alexandre R. Zlotta, Robert G. Bristow and Paul C. Boutros ()
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Michael Fraser: University of Toronto
Julie Livingstone: University of California
Jeffrey L. Wrana: Mount Sinai Hospital
Antonio Finelli: University of Toronto
Housheng Hansen He: Princess Margaret Cancer Centre
Theodorus van der Kwast: University of Toronto
Alexandre R. Zlotta: University of Toronto
Robert G. Bristow: University of Toronto
Paul C. Boutros: University of California

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26489-0

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