Decay of driver mutations shapes the landscape of intestinal transformation.
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Springer Nature
Cancer Research Uk Cambridge Institute
https://doi.org/10.1038/s41586-025-09762-w
Cancer Research Uk Cambridge Institute
https://doi.org/10.1038/s41586-025-09762-w
Abstract
Description
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 proteins1-4. 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.
The authors thank all CRUK CI core facilities and in particular Biological Resource Unit, Genomics, Light Microscopy, Histopathology and Bioinformatics/Statistics. The authors thank the Wellcome Sanger Institute Genomics facility. D.J.W was supported by CRUK Cambridge Institute core funding grant (A24456, Cancer Research UK). D.J.A and K.W. were supported by a Wellcome Trust grant (220540/Z/20/A). J.E., G.L., S.T.M, L.S.S. and N.M. were supported by Innovate UK (10054829, 105858), CRUK (CTRQQR-2021\100006) and Beatson Cancer Charity (24-25-045 BCC). The authors would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of study authors.
The authors thank all CRUK CI core facilities and in particular Biological Resource Unit, Genomics, Light Microscopy, Histopathology and Bioinformatics/Statistics. The authors thank the Wellcome Sanger Institute Genomics facility. D.J.W was supported by CRUK Cambridge Institute core funding grant (A24456, Cancer Research UK). D.J.A and K.W. were supported by a Wellcome Trust grant (220540/Z/20/A). J.E., G.L., S.T.M, L.S.S. and N.M. were supported by Innovate UK (10054829, 105858), CRUK (CTRQQR-2021\100006) and Beatson Cancer Charity (24-25-045 BCC). The authors would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of study authors.