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

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 var...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556363/
https://www.ncbi.nlm.nih.gov/pubmed/34716314
http://dx.doi.org/10.1038/s41467-021-26489-0
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author 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.
author_facet 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.
author_sort Fraser, Michael
collection PubMed
description 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.
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spelling pubmed-85563632021-11-15 Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse 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. Nat Commun Article 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. Nature Publishing Group UK 2021-10-29 /pmc/articles/PMC8556363/ /pubmed/34716314 http://dx.doi.org/10.1038/s41467-021-26489-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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.
Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
title Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
title_full Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
title_fullStr Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
title_full_unstemmed Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
title_short Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
title_sort somatic driver mutation prevalence in 1844 prostate cancers identifies znrf3 loss as a predictor of metastatic relapse
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556363/
https://www.ncbi.nlm.nih.gov/pubmed/34716314
http://dx.doi.org/10.1038/s41467-021-26489-0
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