Order of cancer-driving mutations affects chance of tumour development

New research from the Winton Group has revealed that the order of cancer-driving mutations plays an important role in whether tumours in the intestine can develop.

Colorectal cancers were commonly thought to develop when cells accumulate mutations in a sequence of cancer-promoting genes such as APC, KRAS, and TP53. In this model, an initial mutation in APC is followed by additional mutations that further help a tumour to grow.  

However, recent studies have questioned this simple progression. Cancer-promoting mutations have been found in normal intestinal tissue, and some tumours appear to form through cooperation between neighbouring cells carrying different APC mutations. 

To investigate these patterns more closely, the Winton Group examined how the timing and sequence of mutations affect the earliest stages of tumour development. Using mouse models, the team tested two complementary approaches. 

In the first approach, the team introduced specific cancer-driving mutations into intestinal cells, then exposed tissue to ENU, a compound that induces random mutations. 

In the second approach, ENU was used to create a range of random mutations first before the team then switched on the specific cancer-driving mutations at controlled time points. 

By comparing outcomes, they showed that mutations do not act in isolation. Instead, their effects depend heavily on the genetic environment in which they happen. 

The study, published today in Nature, found that many intestinal cells that do carry cancer-driving mutations are then removed through strong negative selection. Only a small minority survive long enough to influence the future development of a tumour. 

Importantly, some mutations, including certain mutations of the gene APC, appeared to disadvantage cell survival unless they happened after other mutations had already taken place. This suggests that earlier mutations can shape the tissue environment in ways that can then influence whether later cancer-driving mutations are able to push a cell towards becoming cancerous. 

Though more research is needed to understand how this applies in humans, the findings show that early genetic changes can have a significant influence on cancer risk. These insights into how mutation order affects tumour development may help direct future treatment and prevention strategies towards the earliest stages of tumour initiation. 

This work was made possible by the Biological Resource Unit, Genomics, Microscopy, Histopathology and Bioinformatics core facilities at the Cancer Research UK Cambridge Institute.

Dr Filipe Lourenco, First Author and Research Associate at the Cancer Research UK Cambridge Institute said: “This study shows that some mutational events previously thought to occur later in cancer evolution are actually critical for the survival of cells harbouring the tumour-initiating mutations. My future research will focus on understanding why these initiating mutations are negatively selected unless supported by other driver mutations, and on uncovering the nature of these interactions. Together, this will help clarify the early evolutionary steps that lead to tumour formation.”