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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Published inNature 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
LanguageEnglish
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
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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. 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.
AbstractList 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.
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.
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.
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.
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.
ArticleNumber 6248
Author van der Kwast, Theodorus
Zlotta, Alexandre R.
He, Housheng Hansen
Wrana, Jeffrey L.
Bristow, Robert G.
Fraser, Michael
Boutros, Paul C.
Livingstone, Julie
Finelli, Antonio
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SSID ssj0000391844
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Snippet Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic...
Abstract Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate...
Biomarkers of prostate cancer metastasis have been difficult to determine with confidence. Here the authors analyse mutation prevalence in 1844 prostate...
SourceID doaj
pubmedcentral
proquest
crossref
pubmed
springer
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
Publisher
StartPage 6248
SubjectTerms 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
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Title Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
URI https://link.springer.com/article/10.1038/s41467-021-26489-0
https://www.ncbi.nlm.nih.gov/pubmed/34716314
https://www.proquest.com/docview/2588177735
https://pubmed.ncbi.nlm.nih.gov/PMC8556363
https://doaj.org/article/5be08d8b8b2e4398b9561e54a4056765
Volume 12
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