Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse.
Michael FraserJulie LivingstoneJeffrey L WranaAntonio FinelliHousheng Hansen HeTheodorus H Van der KwastAlexandre R ZlottaRobert G BristowPaul C BoutrosPublished in: Nature communications (2021)
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.
Keyphrases
- copy number
- mitochondrial dna
- prostate cancer
- cell cycle
- genome wide
- cell proliferation
- dna methylation
- squamous cell carcinoma
- risk factors
- transcription factor
- stem cells
- electronic health record
- free survival
- neoadjuvant chemotherapy
- gene expression
- lymph node
- microbial community
- benign prostatic hyperplasia
- locally advanced
- antibiotic resistance genes
- nucleic acid