Researchers have created the first complete map of mutations in the CTNNB1 gene that influence tumor development. By testing all possible changes in a critical hotspot, they revealed varying effects on cancer signals. The findings align with patient data and suggest implications for immunotherapy.
A team of scientists has developed a detailed map illustrating how mutations in the CTNNB1 gene, which encodes the protein β-catenin, impact tumor growth. β-catenin normally regulates tissue growth and repair, but when its control fails due to mutations, cells proliferate uncontrollably, a hallmark of cancer.
The study focused on a small hotspot in CTNNB1 where over 70 mutations have been observed across various cancers. In this region, mutations typically prevent the breakdown of β-catenin, allowing it to accumulate and activate genes that promote tumors.
Using mouse stem cells, researchers at the University of Edinburgh tested all 342 possible single-letter mutations in the hotspot. Advanced genome-editing techniques and a fluorescent readout measured each mutation's effect on the β-catenin signaling pathway, which governs cell growth. The results showed a wide range: some mutations caused minor increases in activity, while others dramatically amplified signals.
When compared to genetic data from thousands of cancer patients, the map's predictions matched real-world behaviors. Notably, tumors in different tissues select mutations that produce specific β-catenin activity levels, indicating that location shapes mutation preferences.
In liver cancer, weaker CTNNB1 mutations correlated with higher immune cell presence, whereas stronger ones showed fewer immune cells. This difference could influence responses to immunotherapy.
Andrew Wood, principal investigator at the University of Edinburgh's Institute of Genetics and Cancer, stated: "The new map provides a powerful tool for predicting how specific CTNNB1 mutations affect cancer behaviour and could support the development of more personalised treatments. As the first study to experimentally test every possible mutation in this critical hotspot, it gives scientists a clearer picture of how β-catenin drives tumour growth across different cancer types."
The research, co-led by teams from the University of Edinburgh, Leiden University Medical Center, and Koç University, appears in Nature Genetics. It received funding from the Medical Research Council and the Biotechnology and Biological Sciences Research Council.
