Order of cancer-driving mutations affects the chance of tumour development

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"The order of cancer-driving mutations — genetic changes — plays an important role in whether tumours in the intestine can develop, new research reveals. ...

Using intestinal cells from mice models, the team used two approaches that involved exposing the cells to a compound that causes random mutations. ...

In a new study to investigate these patterns more closely, researchers  ... 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 N-ethyl-N-nitrosourea (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 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. ..."

From the abstract:

"Colorectal cancer (CRC) has traditionally been thought to develop through stepwise mutation of the APC tumour suppressor and other driver genes, coupled with expansion of positively selected clones. However, recent publications show that many premalignant lesions comprise multiple clones expressing different mutant APC proteins.
Here, by mediating transformation on different mouse backgrounds containing mutations in Kras or other common CRC driver genes, we establish that the presence of diverse priming events in the normal mouse intestinal epithelium can change the transformation and clonal-selection landscape, permitting the fixation of strong driver mutations in Apc and Ctnnb1 that are otherwise lost due to negative selection.
These findings, combined with our demonstration of mutational patterns consistent with similar priming events in human CRC, suggest that the order in which driver mutations occur in intestinal epithelium can determine whether clones are positively or negatively selected and can shape subsequent tumour development."

Order of cancer-driving mutations affects the chance of tumour development "Scientists reveal that mutation order influences tumour growth in the intestine."

Decay of driver mutations shapes the landscape of intestinal transformation (open access)

Fig. 1: Tissue priming determines tumour multiplicity in response to ENU [N-ethyl-N-nitrosourea, a highly potent mutagen] mutagenesis.