Year: 2026
Type: article
Study design: Observational Study
Abstract: Aged normal tissues harbour cancer mutations predisposing to transformation. However, how different pro-oncogenic events in the human colon compare in frequency, behaviour and subsequent transformation risk remains unclear. Here, we analyse mutation hotspot regions in five colorectal cancer genes (APC, KRAS, TP53, FBXW7 and CTNNB1) using targeted sequencing of 76,800 normal colonic glands from 56 patients. We show that cancer-driving mutations are present in all genes in histologically normal tissue. Reconstruction of clone dynamics reveals that FBXW7 R465C mutations preferentially become fixed within the tissue, whereas KRAS G12 mutations strongly promote expansion. Modelling mutation order indicates that early loss of both APC copies increasingly favours an APC-first pathway with age, while KRAS activation is equally likely to initiate events in younger individuals. Spatial transcriptomics highlights phenotypic heterogeneity among KRAS mutant clones, with mixed lineage presentation observed only in a subset, a state linked to elevated transformation risk in other organs.
Source: Nature Communications
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1503298539, Wellcome Trust Four year PhD programme in Stem Cell Biology and Medicine, Fundamental and applied biology of intestinal stem cells., Fundamental and applied biology of intestinal stem cells., G2487630569, Wellcome Trust Four year PhD programme in Stem Cell Biology and Medicine, G640145969, G9000328482
OpenAlex ID: W7154574173