Comprehensive mutation map shows effects of key cancer gene

Not all mutations in the CTNNB1 gene – a key cancer driver – are equal, offering insights for personalised cancer treatment.

Researchers have generated all possible (342) mutations in a cancer hotspot region of the gene CTNNB1, which encodes the growth signalling factor β-catenin. This hotspot is important for degrading β-catenin, meaning its mutations can lead to aberrant growth signalling and cancer. The researchers systematically measured the impact of each mutation on cell growth signalling, finding considerable variation even for different mutations at the same position in the gene. They then produced a comprehensive map showing how the mutations affect tumour growth.

'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,' said Dr Andrew Wood, a principal investigator at the University of Edinburgh and a senior co-author on the study. '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.'

Published in Nature Genetics, the researchers used genome editing to introduce each mutation into the CTNNB1 gene in mouse embryonic stem cells. The cells additionally carried a fluorescent reporter to measure growth signalling, allowing the authors to calculate a mutation effect score for every mutation. Given that the hotspot region has the same sequence in the mouse and human gene, the researchers reasoned that the mutation effect scores might similarly reflect human cancers.

Comparing their findings with genetic data from thousands of cancer patients, the researchers showed that the mutation scores reliably predicted the effects of β-catenin mutations in people. They found that cancers in different tissues tend to favour mutations that produce distinct levels of β-catenin activity.

Focusing on liver cancer – where around 20-30 percent of tumours carry CTNNB1 mutations – they observed that cancers with mutations with weaker-effect scores contained more immune cells, whereas those with stronger-effect scores contained fewer. The authors suggest that these effect scores, generated in mouse cells, could be used to predict immunotherapy response in human patients.

The authors note that the systematic design of the study limits the size of genomic regions that can be tested, and this study examines only a small portion of the CTNNB1 gene. Thus, further work is needed to determine whether the mutation effect scores accurately predict β-catenin signalling across cell types beyond mouse embryonic stem cells.