Decay of driver mutations shape the landscape of intestinal transformation

Recent studies have shown that even normal (non-diseased) human colon tissue carries mutations in genes commonly linked to cancer development, such as KRAS or FBXW7. While these mutations alone do not trigger cancer, we hypothesize that they may prime the tissue, making it more susceptible to transforming mutations in genes that activate the WNT pathway (e.g. APC and CTNNB1).The aim of this study was to investigate how different genetic contexts, created by introducing KRAS and other driver mutations into normal mouse intestinal epithelium and then applying ENU mutagenesis, influence the selection and transformation of mutations in Apc and other cancer drivers.We establish that the presence of diverse priming events in 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.