Scientists have developed a comprehensive map that details how hundreds of possible mutations in the CTNNB1 gene impact tumor growth. The CTNNB1 gene encodes β-catenin, a protein involved in tissue growth and repair. Disruptions to β-catenin can lead to uncontrolled cell growth, which is a key characteristic of cancer.
The research focused on a specific 'hotspot' region within CTNNB1 where many cancer-related mutations occur. This region normally serves as a tag for the destruction of β-catenin when it is no longer needed by the cell. Mutations in this area remove the tag, resulting in the accumulation of β-catenin and activation of genes that promote tumor development. Over 70 different mutations have been found in this hotspot across various cancers, but their individual effects were not fully understood.
Researchers from the University of Edinburgh conducted systematic testing of all 342 possible single changes in this hotspot using mouse stem cells, which are suitable for precise genome editing and share similar β-catenin signaling with humans. By employing genome-editing techniques and fluorescent assays, they measured how each mutation influenced activation of the β-catenin pathway—a system responsible for turning on genes that drive cell proliferation.
The findings revealed significant variation among mutations: some only slightly increased β-catenin activity while others caused strong activation. When compared with genetic data from thousands of cancer patients, these mutation scores accurately reflected how β-catenin mutations functioned in human cancers.
The analysis also indicated that different tissues tend to select mutations producing varying levels of β-catenin activity. In liver cancer specifically, two main groups were identified: tumors with weaker CTNNB1 mutations contained more immune cells, while those with stronger mutations had fewer immune cells present. According to researchers, "this suggests that mutation strength may influence how a tumor interacts with the immune system – and potentially how it responds to immunotherapy."
The study was published in Nature Genetics (https://www.nature.com/articles/s41588-025-02496-5) and received support from the Medical Research Council (MRC) and Biotechnology and Biological Sciences Research Council (BBSRC). The work was co-led by teams at the University of Edinburgh, Leiden University Medical Center, and Koç University.
