Related Experiment Video

Updated: Feb 4, 2026

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
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Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling

Anagha Krishna1, Alison Meynert2, Karamjit Singh Dolt3

  • 1The Roslin Institute, University of Edinburgh, Edinburgh, UK.

Nature Genetics
|February 2, 2026
PubMed

Insights

This study maps all possible CTNNB1 mutations, revealing how they activate Wnt signaling. Findings clarify beta-catenin degron function and have implications for cancer therapy and understanding tumor microenvironments.

Area of Science:

  • Molecular Biology
  • Cancer Genomics
  • Biochemistry

Background:

  • CTNNB1 mutations activate the Wnt pathway, driving cancer.
  • Missense mutations in exon 3 are common oncogenic drivers.
  • Understanding these mutations is key for targeted cancer therapies.

Purpose of the Study:

  • To systematically analyze all 342 possible missense mutations in the CTNNB1 degron hotspot.
  • To quantify the signaling phenotypes associated with each mutation.
  • To define the genetic basis of beta-catenin degron function and Wnt pathway activation.

Main Methods:

  • Saturation genome editing coupled with a fluorescent reporter assay.
  • Systematic mutagenesis of the CTNNB1 exon 3 hotspot.
  • Analysis of mutation effect scores and correlation with tumor subclasses.

Main Results:

  • Defined the functional requirements of the beta-catenin degron.
  • Refined the consensus motif for beta-transducin repeat-containing protein (β-TRCP) recognition.
  • Revealed diverse Wnt signaling activation levels for known driver mutations.
  • Identified distinct mutation activity ranges selected in different human cancers.
  • Linked mutation effect scores to distinct hepatocellular carcinoma subclasses and immune infiltration.

Conclusions:

  • Provides a comprehensive resource for understanding CTNNB1 mutational diversity in cancer.
  • Offers insights into the structure-function relationships of the beta-catenin degron.
  • Suggests potential for developing targeted therapies based on mutation-specific Wnt signaling levels.

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