An international team of scientists headed by researchers at the University of Edinburgh, has created a complete map showing how hundreds of possible mutations in a key cancer gene, CTNNB1, influence tumor growth. CTNNB1 is the gene coding for 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 the gene’s “mutation hotspot” in mouse cells, the researchers were able to assign functional scores to more than 80% of CTNNB1 missense mutations observed in cancer. The resulting map helps to explain why certain mutations appear in specific cancers and could guide the development of new treatments.
Andrew Wood, PhD, 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 behavior and could support the development of more personalized 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 tumor growth across different cancer types.”
Wood and colleagues reported on their study in Nature Genetics, in a paper titled “Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling.”
Many cancers carry mutations in a small ‘hotspot’ region of CTNNB1. “CTNNB1, the gene encoding β-catenin, is a frequent target for oncogenic mutations activating the canonical Wnt signaling pathway, typically via missense mutations within a degron hotspot motif in exon 3,” the team explained.
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 tumor 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.
“Gain-of-function changes within the CTNNB1 exon 3 degron motif are among the most common mutations in several tumor types,” the authors continued. “Mutations within exon 3 of CTNNB1 occur in 20-30% of patients with hepatocellular carcinoma (HCC).”
Previous studies have indicated that different CTNNB1 mutations activate signaling to varying extents, they pointed out. “A small subset of exon 3 genotypes observed in human cancer has been directly compared using cellular assays; however, the functional impact of most variants remains unknown.”
For their reported study the researchers 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 signaling 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 signaling system that switches on genes driving cell growth.
The results showed wide variations, with some mutations only slightly increasing β-catenin activity, while others activated the pathway strongly. “Our dataset enables functional interpretation for variants of unknown significance within the CTNNB1 hotspot … and supports reclassification of variants with known relevance in HCC,” the team further pointed out. 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 tumors emerged, those with weaker CTNNB1 mutations, which contained more immune cells, and those with stronger mutations, which had fewer. “In hepatocellular carcinoma, mutation effect scores distinguish two tumor subclasses with different levels of β-catenin signaling, and weaker mutations predict greater immune cell infiltration in the tumor microenvironment,” the researchers stated.
The team says this suggests that mutation strength may influence how a tumor interacts with the immune system—and potentially how it responds to immunotherapy. “Weakly activating exon 3 mutations could provide both a novel mechanism and biomarker for this patient group and help to guide strategies for personalized combination-based therapies,” the scientists suggested.
While noting limitations of the study, they concluded, “Our work therefore provides a resource to understand mutational diversity within a pan-cancer mutation hotspot, with potential implications for targeted therapy … The data explain why particular CTNNB1 mutations are observed in cancer and others are not, despite disrupting residues known to be critical for degron function.”
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