CTNNB1

Overview

CTNNB1 encodes beta-catenin, the key effector of the canonical Wnt signaling pathway and a structural component of the adherens junction complex. Oncogenic missense mutations in CTNNB1 (typically affecting the N-terminal phosphodegron) prevent proteasomal degradation of beta-catenin, resulting in its nuclear accumulation and transcriptional activation of Wnt target genes. CTNNB1 mutations are recurrent across multiple cancer types including endometrial carcinoma, hepatocellular carcinoma, colorectal cancer, and gynecologic malignancies.

Alterations observed in the corpus

  • Missense and multihit mutations in 37% of advanced hepatocellular carcinoma patients by cfDNA profiling (MSK-ACCESS); 92% concordance with paired tissue sequencing; identified as a WNT pathway driver and the second most frequent alteration after TERT promoter mutations PMID:37769223.
  • Mutations less common in Black endometrial carcinoma patients (9% vs. 17% in White patients); associated with endometrioid histology PMID:37651310.
  • Mutated in 15% of dMMR/MSI-H gynecologic cancers (UCEC/OVT) in a nivolumab phase 2 trial; not associated with response or resistance to PD-1 blockade PMID:38653864.
  • Adjusted HR = 2.70 (95% CI: 1.74–4.18, n=65) for cancer-associated VTE by pan-cancer ctDNA liquid biopsy analysis; among the strongest gene-specific VTE associations PMID:39147831.
  • Mutated in LUAD (TSP, n=188); Wnt/beta-catenin pathway member; co-mutated with other Wnt pathway genes including APC and LRP1B. PMID:18948947
  • CTNNB1 GOF mutations in 6% of GBC; identified as potential driver by oncodrive clustering (p.S45F/P); higher frequency in primaries without cholelithiasis (22% vs 4.3%) PMID:36228155
  • CTNNB1 mutations detected in pancreatic cystic neoplasms by whole-exome sequencing, implicating Wnt/beta-catenin pathway activation PMID:22158988
  • HBx destabilizes beta-catenin regulation through GSK3B degradation; Wnt/beta-catenin pathway activated by both HBx and MHBst proteins in HBV-related HCC PMID:22634756
  • Recurrently mutated in medulloblastoma WGS cohort (PCGP, 37 tumors), highlighting Wnt pathway activation as a driver in pediatric brain tumors PMID:22722829
  • CTNNB1 mutations are observed in the Broad melanoma WES cohort of 121 tumors, present in a subset of tumors with active Wnt/beta-catenin signaling PMID:22817889
  • CTNNB1 activating mutations are detected in colorectal adenocarcinoma among 276 TCGA CRC tumors, representing an alternative mechanism of Wnt pathway activation in APC-wild-type tumors PMID:22810696
  • CTNNB1 mutations are the hallmark alteration of the WNT subgroup of medulloblastoma, enriched in WES of 92 tumors (Broad cohort), defining a subgroup with favorable prognosis PMID:22820256
  • CTNNB1 mutations define the WNT subgroup of medulloblastoma in ICGC WGS/WES of 76 tumors, consistently accompanied by monosomy 6 and showing excellent clinical outcomes PMID:22832583
  • Mutated in colorectal cancer WES study (Genentech, 74 tumors) PMID:22895193
  • Mutated in lung adenocarcinoma WES study (Broad, 183 tumors) PMID:22980975
  • Mutated in EAC as part of the beta-catenin pathway, which is altered in only 9% of EACs; an AXIN1-GALNT7 fusion identified by WGS in one tumor PMID:23525077
  • Mutated in 52% of copy-number-low MSS endometrioid endometrial carcinoma; defines this molecular subgroup; mutually exclusive with KRAS and SOX17 mutations PMID:23636398
  • Highlighted in TieDIE/focal-deletion analyses as a downstream pathway and SCNA feature in CCRCC (TCGA, n=446) PMID:23792563
  • Sporadic alteration included in the intrahepatic cholangiocarcinoma/gallbladder carcinoma prevalence-screen panel PMID:24185509
  • Somatic mutations in both pancreatoblastomas (2/2) and in none of the acinar cell carcinomas; reinforces CTNNB1/Wnt-beta-catenin pathway activation as a defining molecular hallmark of pancreatoblastoma PMID:24293293
  • Oncogenic S33/T41 mutations in 3% of PAX-fusion-negative rhabdomyosarcoma (RMS), including one fusion-negative ARMS case; part of a Wnt-pathway signal identified in pediatric RMS genomic landscape PMID:24436047
  • Significantly mutated in muscle-invasive bladder carcinoma (BLCA) identified by COSMIC restriction analysis; one of 32 SMGs from TCGA bladder urothelial carcinoma cohort (n=131) PMID:24476821
  • β-catenin activating mutations in ~30% of HCC and a high-risk feature in HCA for malignant transformation; CTNNB1 mutation in hepatocellular adenoma is an indication for surgical resection per this review PMID:24735922
  • Activating mutation in 29% (range 23–36%) of HCCs (WES, n=1,289); defines canonical-WNT non-proliferation subclass and the immune-excluded class; β-catenin activation drives T-cell exclusion and checkpoint resistance PMID:24798001
  • Beta-catenin pathway alteration among non-hypermutated gastric tumours; alternative splicing strongly associated with U2AF1 S34F mutations PMID:25079317
  • Alternative splicing event strongly associated with U2AF1 S34F mutations in LUAD; U2AF1 S34F drives 129 alternative splicing events including CTNNB1 exon inclusion/exclusion PMID:25079552
  • Recurrently mutated in non-hypermutated CRC (concordant between primary and metastasis per Figure 1B) PMID:25164765
  • Hotspot mutations in 2 MSS carcinosarcoma cases (uterine); indicates Wnt pathway activation in a subset of MSS tumors PMID:25233892
  • Terminal node of Wnt convergence implicated via FAT1/AJUBA/NOTCH1 inactivation in HNSCC (279-tumor TCGA cohort) PMID:25631445
  • Significantly mutated in HCC; central node of WNT/β-catenin pathway (54% pathway alteration); enriched in alcohol/tobacco MSig3 cluster (74% CTNNB1-mutated); mutation frequency rises during tumor progression PMID:25822088
  • Recurrently mutated WNT-pathway component in PDAC; nominating tankyrase inhibitors (XAV939) as therapeutic candidates PMID:25855536
  • WNT pathway hotspot activating mutations observed in mCRPC for the first time (alongside APC, RNF43, ZNRF3, RSPO2) PMID:26000489
  • Recurrent COSMIC mutations (n=3) in Triple-WT cutaneous melanoma subtype PMID:26091043
  • Beta-catenin pathway mutations in primary prostate cancer (TCGA prostate cohort); co-occurs with APC truncating mutations PMID:26544944
  • Mentioned in study PMID:26804919
  • Only one non-hotspot CTNNB1 p.L347P mutation detected among 117 PDTC/ATC thyroid tumors; study explicitly fails to replicate prior reports of frequent WNT-pathway alterations in ATC (also one APC truncation and two unverified AXIN1 variants found) PMID:26878173
  • CTNNB1 beta-catenin activation more common in esophageal adenocarcinoma (EAC) than ESCC in the TCGA multi-platform esophageal carcinoma study PMID:28052061
  • CTNNB1/Wnt signaling activated in PCC/PGL Wnt-altered subtype driven by MAML3 fusions and CSDE1 mutations; beta-catenin antagonists (e.g., PRI-274) proposed as a therapeutic approach PMID:28162975
  • Upregulated expression in Cluster 2 CCA (p < 0.05), alongside WNT5B and AKT1, implicating Wnt pathway activation in this molecular subtype of cholangiocarcinoma PMID:28667006.
  • Hotspot mutations in 86% of WNT-subgroup medulloblastomas; sometimes subclonal alongside subclonal DDX3X variants in the ICGC/CBTTC cohort (n=491) PMID:28726821.
  • Wnt-pathway co-alteration alongside RNF43 and APC in prostate cancer; enriched in metastatic disease states relative to locoregional in the SU2C/PCF pan-cancer prostate cohort PMID:28825054.
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  • Altered in 8% of 1,134 colorectal adenocarcinomas (24% MSI-H, 6% MSS); hotspot N-terminal exon-3 missense mutations (T41A, S45F, S45P) enriched in MSI-H, while large in-frame exon-3 deletions (26 whole-exon, 3 partial) were exclusive to MSS tumors — eliminating GSK3β phosphorylation sites and escaping β-TRCP-mediated degradation to drive nuclear β-catenin PMID:29316426
  • CTNNB1 is an SMG in prostate cancer with N-terminal hotspot mutations plus a novel p.Lys335Ile hotspot near the AXIN-binding domain; confirmed in the 1,013-patient WES cohort and MSK-IMPACT validation PMID:29610475.

Cancer types (linked)

  • HCC: CTNNB1 mutations in 37% of advanced HCC by cfDNA (MSK-ACCESS); WNT pathway driver; high concordance with tissue sequencing PMID:37769223.
  • UCEC/UCS: CTNNB1 mutations enriched in endometrioid histology; less common in Black patients consistent with their lower proportion of endometrioid ECs PMID:37651310.
  • UCEC/OVT: CTNNB1 mutations in 15% of dMMR gynecologic cancers; not a biomarker for nivolumab response PMID:38653864.
  • Pan-cancer: CTNNB1 mutations in ctDNA associated with markedly elevated VTE risk (adjusted HR 2.70); one of the strongest individual gene-level VTE associations across tumor types PMID:39147831.

Co-occurrence and mutual exclusivity

  • In HCC, CTNNB1 mutations co-occur with TERT promoter mutations as the two most frequent alterations detected in cfDNA PMID:37769223.
  • In endometrial carcinoma, CTNNB1 mutations associate with endometrioid histology and the POLE/MSI-H molecular subtypes rather than the CN-H/TP53abn subtype PMID:37651310.

Therapeutic relevance

  • CTNNB1 mutations were not associated with response to nivolumab in dMMR gynecologic cancers, limiting their utility as predictive biomarkers for checkpoint inhibitor therapy in this context PMID:38653864.
  • CTNNB1 mutations in ctDNA are among the strongest VTE risk signals; their presence may inform prophylactic anticoagulation decision-making PMID:39147831.
  • No direct CTNNB1-targeted therapies are approved; beta-catenin nuclear accumulation has been targeted by porcupine inhibitors and other Wnt pathway inhibitors in clinical trials.

Open questions

  • The mechanism by which CTNNB1 mutations confer elevated VTE risk (HR 2.70) independent of other cancer characteristics is not understood PMID:39147831.
  • CTNNB1 mutations are associated with immune-excluded tumor microenvironments in some cancers; whether this contributes to resistance to nivolumab in dMMR UCEC warrants further study PMID:38653864.

Sources

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This page was processed by entity-page-writer on 2026-05-15. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15. - PMID:28726821

This page was processed by wiki-cli on 2026-05-15. - PMID:28825054

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This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

This page was processed by wiki-cli on 2026-05-15. - PMID:29610475

This page was processed by wiki-cli on 2026-05-15.