Scientists have created a complete map showing how hundreds of possible mutations in a key cancer gene influence tumour growth.
The study focused on CTNNB1, a gene that produces the protein β-catenin, which helps regulate tissue growth and repair. When β-catenin is disrupted, cells can begin uncontrolled growth – a hallmark of cancer.
By systematically testing all possible mutations in a priority area of the gene in mouse cells, the map helps explain why certain mutations appear in specific cancers and could guide the development of new treatments, experts say.
Many cancers carry mutations in a small 'hotspot' region of CTNNB1. Normally, this region acts like a tag that marks β-catenin for destruction when it is no longer needed.
Mutations in the hotspot remove this tag, causing β-catenin to accumulate and activate genes that drive tumour growth. More than 70 different mutations have been observed within this hotspot in different types of cancer, but it was not known whether different mutations influenced cancer growth in different ways.
In the study, researchers from the University of Edinburgh tested all 342 possible single changes in this hotspot using mouse stem cells. These cells are particularly well suited to precise genome editing, and β-catenin signalling is highly conserved between mice and humans.
Using genome-editing tools and a fluorescent test, the team measured how strongly each mutation activates the β-catenin pathway – a signalling system that switches on genes driving cell growth. The results showed wide variation: some mutations only slightly increased β-catenin activity, while others activated the pathway strongly.
By comparing their results with genetic data from thousands of cancer patients, the researchers showed that the mutation scores accurately predicted the effects of β-catenin mutations in people. The analysis also revealed that cancers arising in different tissues tend to select mutations that generate different levels of β-catenin activity.
In liver cancer, two major groups of tumours emerged: those with weaker CTNNB1 mutations, which contained more immune cells, and those with stronger mutations, which had fewer. Researchers say this suggests that mutation strength may influence how a tumour interacts with the immune system – and potentially how it responds to immunotherapy.
Andrew Wood, Principal Investigator at the University of Edinburgh's Institute of Genetics and Cancer, said: "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 study is published in Nature Genetics: https://www.nature.com/articles/s41588-025-02496-5 [URL will become active when embargo lifts] and was supported by the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC). The study was co-led by researchers from the University of Edinburgh, Leiden University Medical Center and Koç University.
