Cancer is often thought of as a single disease, but at the genetic level, tumours arising in the same organ can behave in remarkably different ways. A new article led by senior researcher Dr. Derya Deniz Özdemir from Koç University School of Medicine and the Research Center for Translational Medicine (KUTTAM), published in Nature Genetics , shows that mutations in one of the most frequently altered genes in cancer do not all act in the same way, and that the strength of a mutation can shape how a tumour interacts with the immune system.The gene in question is CTNNB1, which provides the instructions for building a protein called β-catenin. Under normal circumstances, β-catenin is kept in check by a cellular "destruction complex" that tags it for removal. When this system fails, either through mutations in the destruction complex itself or through changes directly in CTNNB1, β-catenin accumulates, enters the cell's nucleus, and switches on genes that drive cell growth. This is one of the keyways cancers can hijack normal biology.
The researchers, led by teams at the University of Edinburgh, UMC Leiden and Koç University, used a powerful gene-editing technique called saturation genome editing to systematically test every single possible mutation within a critical region of CTNNB1 known as the “degron hotspot”. Rather than studying one mutation at a time, they introduced all 342 possible changes into mouse stem cells simultaneously and measured how strongly each one activated β-catenin signalling. The result was a comprehensive map revealing that these mutations span a wide spectrum, from barely perceptible increases in signalling to dramatic activation.
One of the study's key findings is that tumours in different body sites do not select mutations randomly. Instead, each tissue appears to favour mutations that push β-catenin signalling to a particular level, a concept sometimes called "just-right" signalling. Cancers of the central nervous system, for example, tend to harbour stronger mutations, while kidney tumours cluster around weaker ones. This strongly suggests that the tissue environment actively shapes which mutations are advantageous during tumour development.
Perhaps the most clinically significant finding concerns liver cancer, or hepatocellular carcinoma. The team showed that patients whose tumours carry weaker CTNNB1 mutations have significantly more immune cells infiltrating their tumours compared to those with stronger mutations. Because β-catenin signalling is known to suppress anti-tumour immunity, this makes intuitive sense: lower signalling allows the immune system to engage more effectively. This distinction could prove critical for treatment decisions, as tumours with more immune infiltration are generally more likely to respond to immunotherapy.
Ultimately, this study demonstrates that a single mutation hotspot can generate a rich diversity of tumour behaviours, and that understanding the precise strength of each mutation, rather than simply its presence or absence, opens the door to more personalised cancer treatment strategies.
Nature Genetics
Experimental study
Cells
Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling
2-Feb-2026
The authors declare no competing interests.