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

• Published in: Nature communications Vol. 12; no. 1; pp. 6248 - 15
• Main Authors: Fraser, Michael, Livingstone, Julie, Wrana, Jeffrey L., Finelli, Antonio, He, Housheng Hansen, van der Kwast, Theodorus, Zlotta, Alexandre R., Bristow, Robert G., Boutros, Paul C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.10.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 45/91; 631/67/1857; 631/67/322; 631/67/589/466; 631/67/69; Biomarkers; Biomarkers, Tumor - genetics; Castration; Cell cycle; Cell Cycle - genetics; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Copy number; Gene Expression Regulation, Neoplastic; Genomic instability; Humanities and Social Sciences; Humans; Male; Metastases; Metastasis; mRNA; multidisciplinary; Mutation; Myc protein; Neoplasm Recurrence, Local - genetics; Nucleotides; p53 Protein; Prevalence; Prognosis; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Science; Science (multidisciplinary); Tumors; Ubiquitin-Protein Ligases - genetics; Wnt protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26489-0

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. Biomarkers of prostate cancer metastasis have been difficult to determine with confidence. Here the authors analyse mutation prevalence in 1844 prostate cancers and show that ZNRF3 loss is enriched in metastatic, castration-resistant prostate cancer and associated with metastasis of localized disease.