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; Paul C Boutros

doi:10.1038/s41467-021-26489-0

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

Nat Commun. 2021 Oct 29;12(1):6248. doi: 10.1038/s41467-021-26489-0.

Authors

Michael Fraser^{1

2

3}, Julie Livingstone^{4

5

6

7}, Jeffrey L Wrana^{8

9}, Antonio Finelli^{10

11

12}, Housheng Hansen He^{12

13}, Theodorus van der Kwast^{14

15}, Alexandre R Zlotta^{10

11

8

9}, Robert G Bristow^{13

16

17}, Paul C Boutros^{18

19

20

21

22

23}

Affiliations

¹ Department of Surgery, Division of Urology, University of Toronto, Toronto, ON, Canada. michael.fraser@cpcgene.com.
² Department of Surgical Oncology, Genitourinary Site Group, Princess Margaret Cancer Centre, Toronto, ON, Canada. michael.fraser@cpcgene.com.
³ Ontario Institute for Cancer Research, Toronto, ON, Canada. michael.fraser@cpcgene.com.
⁴ Department of Human Genetics, University of California, Los Angeles, CA, USA.
⁵ Department of Urology, University of California, Los Angeles, CA, USA.
⁶ Institute for Precision Health, University of California, Los Angeles, CA, USA.
⁷ Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA, USA.
⁸ Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
⁹ Mount Sinai Hospital, Sinai Health System, Toronto, Canada.
¹⁰ Department of Surgery, Division of Urology, University of Toronto, Toronto, ON, Canada.
¹¹ Department of Surgical Oncology, Genitourinary Site Group, Princess Margaret Cancer Centre, Toronto, ON, Canada.
¹² Princess Margaret Cancer Centre, Toronto, ON, Canada.
¹³ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁵ Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
¹⁶ Manchester Cancer Research Centre, Manchester, UK.
¹⁷ University of Manchester, Manchester, UK.
¹⁸ Department of Human Genetics, University of California, Los Angeles, CA, USA. PBoutros@mednet.ucla.edu.
¹⁹ Department of Urology, University of California, Los Angeles, CA, USA. PBoutros@mednet.ucla.edu.
²⁰ Institute for Precision Health, University of California, Los Angeles, CA, USA. PBoutros@mednet.ucla.edu.
²¹ Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA, USA. PBoutros@mednet.ucla.edu.
²² Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. PBoutros@mednet.ucla.edu.
²³ Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada. PBoutros@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics*
Cell Cycle / genetics
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Gene Expression Regulation, Neoplastic
Humans
Male
Mutation*
Neoplasm Recurrence, Local / genetics
Prevalence
Prognosis
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / pathology*
Ubiquitin-Protein Ligases / genetics*

Substances

Biomarkers, Tumor
Cell Cycle Proteins
PRC1 protein, human
Ubiquitin-Protein Ligases
ZNRF3 protein, human

Associated data

figshare/10.6084/m9.figshare.16574486.v1

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding