Clonal biases dictate availability of colonic cancer driver mutations for transformation

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.

Metadata

Item Type:	Article
Authors/Creators:	Skoufou-Papoutsaki, N. Kemp, R. Adler, S. Marks, K. https://orcid.org/0000-0003-2753-6238 Girard, A.-C. Mehmed, S. Lourenço, F.C. Moutin, E.B. Ten Hoopen, R. Morrissey, E. Winton, D.J. Tourigny, D.S.
Copyright, Publisher and Additional Information:	© The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 3 April 2026 Published (online): 16 April 2026 Published: 16 April 2026
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds)
Funding Information:	Funder Grant number MRC MR/T027908/1 Pathological Society Of Great Britain & Ireland JSPS CLSG 2021 0421 01 Cancer Research UK Supplier No: 138573 A28063
Date Deposited:	26 Jun 2026 14:39
Last Modified:	26 Jun 2026 14:39
Status:	Published
Publisher:	Springer Nature
Identification Number:	10.1038/s41467-026-71944-5
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:242406

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Clonal biases dictate availability of colonic cancer driver mutations for transformation

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