RNF43

Overview

RNF43 is an E3 ubiquitin ligase that negatively regulates Wnt signaling by promoting ubiquitin-mediated degradation of Frizzled receptors. Loss-of-function mutations in RNF43 lead to constitutive Wnt pathway activation and are recurrent in colorectal, pancreatic, and endometrial cancers. RNF43-mutant tumors may be sensitive to Wnt pathway inhibitors (e.g., porcupine inhibitors).

Alterations observed in the corpus

  • RNF43 mutations are highly frequent co-alterations in BRAF fusion-positive colorectal cancers (64% of BRAF-fusion CRCs), co-occurring with TP53 (57%), KMT2D (43%), MSH3 (42%), and ARID1A (36%) PMID:38922339.
  • RNF43 mutations observed in prostate cancer patient-derived xenografts (PDXs) in heterogeneity pair 316, functioning as a negative regulator of the Wnt pathway; identified as a driver alteration in this model PMID:38488813.
  • RNF43 is listed as an altered gene in the cervical cancer genomic landscape cohort (N=177), where Wnt pathway alterations are implicated in a subset of cases PMID:37643132.
  • RNF43 alterations independently associated with shorter first-line OS in metastatic PDAC patients receiving chemotherapy (HR_adj = 2.79, P_adj = 0.047; median 6.6 vs 10.8 months); trend toward higher KRAS mutant-allele gain frequency in RNF43-mutant tumors (67% vs 30%, P = 0.2), though the trend was not statistically significant. PMID:39753968
  • WES of pancreatic cystic neoplasms identified recurrent RNF43 mutations in intraductal papillary mucinous neoplasms (IPMNs), establishing it as a candidate tumor suppressor in pancreatic cystic lesions PMID:22158988
  • Ubiquitin ligase upregulated in colon cancer; colon-specific expression pattern in NCI-60 cell lines identified via CellMiner drug-pattern comparison analysis PMID:22802077
  • RNF43 somatic mutation in 1/23 (4%) pancreatic carcinomas with acinar differentiation; previously associated with IPMN and mucinous cystic neoplasms PMID:24293293
  • Identified as a significantly mutated gene in gastric cancer (TCGA); functions as a WNT pathway negative regulator (RING-domain E3 ubiquitin ligase that promotes Frizzled receptor degradation). PMID:25079317
  • Mutated in 6% of pancreatic ductal adenocarcinoma cases; WNT-pathway tumour suppressor; mutations predict sensitivity to porcupine inhibitors (LGK974). PMID:25855536
  • Mutated in metastatic castration-resistant prostate cancer (mCRPC); WNT-pathway tumour suppressor; mutually exclusive with APC alterations; combined with ZNRF3, predicted to confer sensitivity to porcupine inhibitors. PMID:26000489
  • Known CRC driver identified as a source of recurrent neopeptides (Table S6) in the 619-case colorectal carcinoma WES cohort (NHS/HPFS); frameshift indels in RNF43 generate a disproportionately high share of predicted neoantigens. PMID:27149842
  • CTNNB1 and RNF43 identified as Wnt-pathway co-alterations alongside APC in advanced prostate cancer (locoregional through mCRPC) PMID:28825054
  • Altered in 9% of mCRC; right-sided enrichment observed in MSS mCRC in a 1,640-tumor targeted sequencing cohort PMID:29316426

Cancer types (linked)

  • Colorectal cancer (COAD) — RNF43 mutations in 64% of BRAF fusion-positive CRCs; enrichment in this molecular subtype with co-occurring Wnt pathway activation PMID:38922339.
  • Prostate cancer (PRAD) — RNF43 mutation in PDX model heterogeneity pair 316; negative regulator of Wnt pathway in this context PMID:38488813.
  • Cervical cancer (CESC) — RNF43 alterations observed in the MSK cervical cancer cohort PMID:37643132.
  • Pancreatic adenocarcinoma (PAAD) — RNF43 alterations independently predict shorter first-line OS in metastatic chemotherapy-treated PDAC (HR_adj = 2.79, P_adj = 0.047), with a trend toward higher KRAS mutant-allele dosage. PMID:39753968

Co-occurrence and mutual exclusivity

  • Strong co-occurrence with BRAF fusions in colorectal cancer (64%); likely represents a distinct CRC molecular subtype with concurrent Wnt pathway loss and MAPK pathway activation PMID:38922339.
  • Co-occurs with SPOP mutations in prostate cancer PDX heterogeneity model 316 PMID:38488813.

Therapeutic relevance

  • RNF43-mutant tumors with Wnt pathway activation may be candidates for porcupine inhibitor therapy (e.g., WNT974, LGK974); the co-occurrence with BRAF fusions in CRC creates a potentially dual-pathway targetable scenario PMID:38922339.

Open questions

  • Whether the high RNF43 mutation rate in BRAF-fusion colorectal cancers is causally linked to the co-occurrence or represents a shared etiological mechanism (e.g., microsatellite instability) is not established.
  • Clinical activity of porcupine inhibitors in RNF43-mutant prostate cancer PDXs has not been reported in the corpus.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:22158988

This page was processed by crosslinker on 2026-05-14. - PMID:22802077

This page was processed by crosslinker on 2026-05-14. - PMID:24293293

This page was processed by crosslinker on 2026-05-14. - PMID:25079317

This page was processed by crosslinker on 2026-05-14. - PMID:25855536

This page was processed by crosslinker on 2026-05-14. - PMID:26000489

This page was processed by crosslinker on 2026-05-14. - PMID:27149842

This page was processed by wiki-cli on 2026-05-14. - PMID:28825054

This page was processed by entity-page-writer on 2026-05-15. - PMID:29316426

This page was processed by entity-page-writer on 2026-05-15.