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

Michael Fraser,Theodorus Van Der Kwast,Robert G Bristow,Jeffrey L Wrana,Alexandre R Zlotta,Housheng Hansen He,Julie Livingstone,Paul C Boutros,Antonio Finelli

doi:10.1038/s41467-021-26489-0

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.

Highlights

Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer than localized disease represent candidate prognostic biomarkers
This suggests that mutations that are highly prevalent in lethal metastatic, castration-resistant prostate cancer but rare in localized disease may be prognostic biomarkers that reflect the elevated risk of occult metastatic disease
We collected somatic single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) calls from eleven DNA sequencing studies of prostate cancer comprising 1844 patients (1289 localized, 555 metastatic; Fig. S1 and S2 and Supplementary Data 1)[7,11,12,13,14,15,18,19,20,21,22]

Summary

Introduction

Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We identify the differential prevalence of seventy-three established driver mutations, including mutations in the androgen receptor and its enhancer region Amongst these differentially prevalent driver mutations, twenty-four are present in at least 5% of localized cancers and four are significantly associated with metastatic relapse of localized disease, including genomic gains in MYC and CCND1. Genomic loss of the WNT pathway inhibitor ZNRF3 is associated with WNT pathway activity and predicts biochemical and metastatic relapse and overall survival in localized prostate cancer. These results demonstrate a method of identifying candidate prognostic genomic biomarkers by comparing primary and metastatic disease and establish ZNRF3 loss as a predictor of aggressive localized prostate cancer

Methods

Results

Conclusion