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.
Growth trigger
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.
Mutation mapping
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.
Accurate prediction
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.
The study is published in Nature Genetics 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.