Decay of driver mutations shapes the landscape of intestinal transformation

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.

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Publication Details

Journal
Nature
Published
2025-12-03
DOI
https://doi.org/10.1038/s41586-025-09762-w
Citations
2
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
2.94
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article

Decay of driver mutations shapes the landscape of intestinal transformation

Stephen T. McSorley, Sam Adler, Iannish Sadien, Richard Kemp et al.
2 citations
Nature
Genetic factors in colorectal cancer
2.94
article

Decay of driver mutations shapes the landscape of intestinal transformation

Stephen T. McSorley, Sam Adler, Iannish Sadien, Richard Kemp, Gerard Lynch, Douglas J. Winton, Lee Hazelwood, Filipe C. Lourenço, Kim Wong, Ashley Sawle, Joanne Edwards, Noori Maka, Giada Giavara, Leonor Schubert Santana, David J. Adams, Matthew Eldridge, Anna M. Nicholson
article en
2 citations

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.

NatureVol. 649(8097)
University of Cambridge (GB), NHS Greater Glasgow and Clyde (GB), Beatson West of Scotland Cancer Centre (GB), Cancer Research UK (GB), Wellcome Sanger Institute (GB), Cancer Research UK Cambridge Center (GB), Queen Elizabeth University Hospital (GB)
Openalex Percentile: Top 8%
Genetic factors in colorectal cancer
2.94
DOIOpen Access PDFOpenAlex
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