ZNRF3

Overview

ZNRF3 is an E3 ubiquitin ligase that negatively regulates WNT/β-catenin signalling by targeting Frizzled receptors for degradation. In cancer genomics, it has been identified as a recurrently mutated WNT-pathway component in both hepatocellular carcinoma and metastatic castration-resistant prostate cancer.

Alterations observed in the corpus

  • Newly highlighted as a recurrently mutated β-catenin pathway inhibitor in hepatocellular carcinoma (alongside USP34 and MACF1); part of the WNT/β-catenin pathway (54% altered) in HCC. PMID:25822088
  • Mutated in metastatic castration-resistant prostate cancer (mCRPC); WNT-pathway component mutually exclusive with APC alterations; combined with RNF43, predicted to confer sensitivity to porcupine inhibitors; R-spondin antibodies may also be warranted. PMID:26000489

Cancer types (linked)

  • HCC: Recurrently mutated β-catenin pathway inhibitor; part of WNT pathway alteration in 54% of cases. PMID:25822088
  • PRAD (mCRPC): Mutated in mCRPC; mutually exclusive with APC alterations; part of WNT-pathway landscape with predicted porcupine-inhibitor sensitivity. PMID:26000489

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • ZNRF3/RNF43 mutations (6% combined with RNF43 in mCRPC) are predicted to confer sensitivity to porcupine inhibitors; R-spondin antibodies may also warrant investigation. PMID:26000489

Open questions

  • Individual mutation frequency of ZNRF3 vs. RNF43 in mCRPC not separately reported; combined frequency is 6%. PMID:26000489

Sources

This page was processed by crosslinker on 2026-05-14.