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 in | Nature communications Vol. 12; no. 1; pp. 6248 - 15 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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Nature Publishing Group UK
29.10.2021
Nature Publishing Group Nature Portfolio |
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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 |
Author_xml | – sequence: 1 givenname: Michael surname: Fraser fullname: Fraser, Michael email: michael.fraser@cpcgene.com organization: Department of Surgery, Division of Urology, University of Toronto, Department of Surgical Oncology, Genitourinary Site Group, Princess Margaret Cancer Centre, Ontario Institute for Cancer Research – sequence: 2 givenname: Julie orcidid: 0000-0002-8424-3768 surname: Livingstone fullname: Livingstone, Julie organization: Department of Human Genetics, University of California, Department of Urology, University of California, Institute for Precision Health, University of California, Jonsson Comprehensive Cancer Centre, University of California – sequence: 3 givenname: Jeffrey L. orcidid: 0000-0003-0932-0644 surname: Wrana fullname: Wrana, Jeffrey L. organization: Lunenfeld Research Institute, Mount Sinai Hospital, Mount Sinai Hospital, Sinai Health System – sequence: 4 givenname: Antonio surname: Finelli fullname: Finelli, Antonio organization: Department of Surgery, Division of Urology, University of Toronto, Department of Surgical Oncology, Genitourinary Site Group, Princess Margaret Cancer Centre, Princess Margaret Cancer Centre – sequence: 5 givenname: Housheng Hansen surname: He fullname: He, Housheng Hansen organization: Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto – sequence: 6 givenname: Theodorus orcidid: 0000-0001-8640-5786 surname: van der Kwast fullname: van der Kwast, Theodorus organization: Department of Laboratory Medicine and Pathobiology, University of Toronto, Laboratory Medicine Program, University Health Network – sequence: 7 givenname: Alexandre R. surname: Zlotta fullname: Zlotta, Alexandre R. organization: Department of Surgery, Division of Urology, University of Toronto, Department of Surgical Oncology, Genitourinary Site Group, Princess Margaret Cancer Centre, Lunenfeld Research Institute, Mount Sinai Hospital, Mount Sinai Hospital, Sinai Health System – sequence: 8 givenname: Robert G. orcidid: 0000-0002-8553-9544 surname: Bristow fullname: Bristow, Robert G. organization: Department of Medical Biophysics, University of Toronto, Manchester Cancer Research Centre, University of Manchester – sequence: 9 givenname: Paul C. orcidid: 0000-0003-0553-7520 surname: Boutros fullname: Boutros, Paul C. email: PBoutros@mednet.ucla.edu organization: Department of Human Genetics, University of California, Department of Urology, University of California, Institute for Precision Health, University of California, Jonsson Comprehensive Cancer Centre, University of California, Department of Medical Biophysics, University of Toronto, Department of Pharmacology & Toxicology, University of Toronto |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34716314$$D View this record in MEDLINE/PubMed |
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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... |
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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 |
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