Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling

CTNNB1, the gene encoding β-catenin, is a frequent target for oncogenic mutations activating the canonical Wnt signaling pathway, typically through missense mutations within a degron hotspot motif in exon 3. Here, we combine saturation genome editing with a fluorescent reporter assay to quantify signaling phenotypes for all 342 possible missense mutations in the mutation hotspot. Our data define the genetic requirements for β-catenin degron function, refine the consensus motif for substrate recognition by β-TRCP and reveal diverse levels of signal activation among known driver mutations. Tumorigenesis in different human tissues involves selection for CTNNB1 mutations spanning distinct ranges of predicted activity. In hepatocellular carcinoma, mutation effect scores distinguish two tumor subclasses with different levels of β-catenin signaling, and weaker mutations predict greater immune cell infiltration in the tumor microenvironment. Our work provides a resource to understand mutational diversity within a pan-cancer mutation hotspot, with potential implications for targeted therapy.

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Publication Details

Journal
Nature Genetics
Published
2026-02-01
DOI
https://doi.org/10.1038/s41588-025-02496-5
Primary Topic
Wnt/β-catenin signaling in development and cancer
Type
article
Field-Weighted Citation Impact
0.00
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article

Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling

Agavni Mesropian, Conny Brouwers, Hannes Becher, Albert Gris‐Oliver et al.
Nature Genetics
Wnt/β-catenin signaling in development and cancer
article

Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling

Agavni Mesropian, Conny Brouwers, Hannes Becher, Albert Gris‐Oliver, Jill Claassens, Margot M. Linssen, Roser Pinyol, Gillian C.A. Taylor, Ryan Silk, Anna Ferrer-Vaquer, Philippe Emmanuel Gautier, Singh Dolt Karamjit, Alison M Meynert, Thomas Graham Bird, Joseph A. Marsh, Ailith Ewing, Martijn Kelder, Derya D. Ozdemir, Andrew J. Wood, Shahida Sheraz, Josep M. Llovet, Anagha Krishna, Graeme Grimes, Colin A. Semple, Timothy J. Kendall, Peter Hohenstein
article en

Abstract

CTNNB1, the gene encoding β-catenin, is a frequent target for oncogenic mutations activating the canonical Wnt signaling pathway, typically through missense mutations within a degron hotspot motif in exon 3. Here, we combine saturation genome editing with a fluorescent reporter assay to quantify signaling phenotypes for all 342 possible missense mutations in the mutation hotspot. Our data define the genetic requirements for β-catenin degron function, refine the consensus motif for substrate recognition by β-TRCP and reveal diverse levels of signal activation among known driver mutations. Tumorigenesis in different human tissues involves selection for CTNNB1 mutations spanning distinct ranges of predicted activity. In hepatocellular carcinoma, mutation effect scores distinguish two tumor subclasses with different levels of β-catenin signaling, and weaker mutations predict greater immune cell infiltration in the tumor microenvironment. Our work provides a resource to understand mutational diversity within a pan-cancer mutation hotspot, with potential implications for targeted therapy.

Nature GeneticsVol. 58(2)
Institució Catalana de Recerca i Estudis Avançats (ES), Leiden University (NL), Memorial Sloan Kettering Cancer Center (US), Roslin Institute (GB), Koç University (TR), University of Applied Sciences Leiden (NL), Leiden University Medical Center (NL), Beatson West of Scotland Cancer Centre (GB), Cancer Research UK (GB), Edinburgh Cancer Research (GB), Departament de Salut (ES), Centre for Inflammation Research (GB), Institute of Genetics and Cancer (GB), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Universitat de Barcelona (ES), University of Edinburgh (GB), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 70%
Wnt/β-catenin signaling in development and cancer
DOIOpen Access PDFOpenAlex
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