Genetic Context Shapes Selection or Decay of Driver Mutations in Colon Cancer

The tumor suppressor APC is the most frequently mutated gene in colorectal cancer (CRC), and its loss is a defining early event that activates WNT signaling and drives clonal expansion. CRC has traditionally been viewed as a stepwise process: APC mutation, accumulation of additional driver mutations, and clonal outgrowth. However, recent studies reveal that early lesions often harbor multiple coexisting APC-mutant clones, indicating that different APC mutations create selective niches that shape how subsequent oncogenic events are acquired. In this study, Lourenço and colleagues dissect how APC mutations and their interaction with other oncogenic mutations shape clonal selection and transformation in the intestinal epithelium. To model how driver mutations shape the intestinal epithelium, the authors engineered mice carrying single or combined oncogenic alterations and performed ENU mutagenesis, revealing that tumor development and driver selection are context-dependent. Apc-heterozygous primed mice favored additional Apc mutations and often generated polyclonal lesions, whereas KrasG12D and other contexts selected for Ctnnb1-driven tumors. Ctnnb1 drivers were mostly exon 3 missense mutations clustered at residues regulating β-catenin degradation, with prevalence influenced by intrinsic mutational susceptibility and positive selection. Apc truncations were widely distributed, but the Armadillo regions were enriched, whereas N-terminal regions were disfavored. In rescue experiments where ENU-induced mutations were introduced before oncogenic priming, most Apc- and Ctnnb1-driven clones failed to persist, indicating strong negative selection in unprimed tissue. For the clones that did survive, Apc mutations decayed differently by location. N-terminal truncations were rapidly lost, and C-terminal mutations decayed neutrally. This region-specific selection was reflected in human CRCs, with APC mutations enriched in the mutation cluster region and depleted in the Armadillo domain, suggesting conserved constraints on which early lesions persist to drive transformation. Together, these findings show that the CRC transformation landscape is shaped by mutagenesis and selective constraints, wherein WNT-dysregulating mutations, particularly APC loss, create a “sweet spot” for clonal expansion.Lourenço FC, Sadien, ID, Wong K, Adler S, Sawle A, Schubert Santana L, et al. Decay of driver mutations shapes the landscape of intestinal transformation. Nature 2025 Dec 3 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.