Overview
- Researchers systematically tested all 342 possible missense changes in the CTNNB1 degron hotspot using saturation genome editing in mouse embryonic stem cells with a fluorescent β-catenin reporter.
- Quantitative effect scores showed a wide spectrum of β-catenin activation, with very strong effects at positions 32–37 and weaker effects at S45, and differing outcomes from specific substitutions at the same residue such as T41.
- Linking the functional map to human tumor datasets revealed tissue-specific selection consistent with a 'just-right' signaling model, including stronger mutations in central nervous system cancers and weaker ones in kidney tumors.
- In hepatocellular carcinoma, tumors harboring weaker CTNNB1 mutations displayed greater immune-cell infiltration than those with stronger mutations, suggesting potential relevance for immunotherapy response.
- The study, led by teams at the University of Edinburgh, Leiden University Medical Center and Koç University and published in Nature Genetics, offers predictive insights while the authors call for validation across additional human cell types and clinical cohorts before clinical use.