Cancer is often thought of as a single disease. Yet even tumours that arise in the same organ can follow very different genetic paths.
A new study shows that these differences can sometimes be traced back to tiny changes in a single gene. Research 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, reveals that mutations in one of the most frequently altered genes in cancer do not all have the same effect. The findings suggest that it is not only the presence of a mutation that matters, but also how strongly it alters cellular signalling, which may influence how tumours interact 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 tightly controlled by a cellular “destruction complex” that marks it for removal when its levels become too high. This system acts like a braking mechanism that keeps cell growth under control. When the system fails, either because the destruction complex itself is mutated or because CTNNB1 is altered, β-catenin begins to accumulate. It then enters the cell’s nucleus and switches on genes that promote cell growth. This process allows cancer cells to hijack normal cellular machinery and drive uncontrolled proliferation.
To understand how different mutations influence this process, researchers from the University of Edinburgh, UMC Leiden and Koç University used an advanced gene-editing method known as saturation genome editing. Instead of studying one mutation at a time, the team systematically tested all 342 possible mutations within a critical region of CTNNB1 known as the “degron hotspot.” They introduced these changes into mouse stem cells and measured how strongly each mutation activated β-catenin signalling.
The result was a comprehensive map showing that these mutations vary dramatically in their effects. Some caused only very small increases in signalling, while others triggered powerful activation of cell-growth pathways.
One of the study’s most striking findings is that tumours in different organs do not select mutations randomly. Instead, each tissue appears to favour mutations that push β-catenin signalling to a specific level. Scientists sometimes describe this phenomenon as “just-right” signalling: tumours tend to evolve mutations that produce signalling levels that are neither too weak nor excessively strong, but just sufficient to support tumour behaviour.
For example, cancers of the central nervous system tend to carry stronger mutations, while kidney tumours more often cluster around weaker ones. This suggests that the local tissue environment plays an active role in determining which mutations provide an advantage during tumour development.
One of the most clinically relevant findings emerged in liver cancer, also known as hepatocellular carcinoma. The researchers discovered that tumours carrying weaker CTNNB1 mutations contained significantly more immune cells than tumours with stronger mutations.
This observation fits well with what scientists already know about β-catenin signalling: strong β-catenin activity can suppress the immune system’s ability to attack tumours. When signalling is weaker, immune cells appear to enter the tumour more easily, allowing the body’s natural defences to engage more effectively.
This distinction could be highly important for treatment decisions. Tumours that contain more immune cells are generally more likely to respond to immunotherapy, treatments that stimulate the immune system to recognise and destroy cancer cells.
Ultimately, the study demonstrates that even a single mutation hotspot can produce a wide spectrum of tumour behaviours. Understanding not just whether a mutation is present, but how strongly it affects cellular signalling, may therefore help guide more precise and personalised cancer treatment strategies in the future.