Decay of driver mutations shapes the landscape of intestinal transformation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41339549.
- Also identified by DOI 10.1038/s41586-025-09762-w and PMC identifier 12804087.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>1-4</sup>. 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.
Medical subject headings
- Cell Transformation, Neoplastic
- Mutation
- Colorectal Neoplasms
- Intestinal Mucosa