Haploinsufficient phenotypes promote selection of PTEN and ARID1A-deficient clones in human colon

Abstract

Cancer driver mutations are defined by their high prevalence in cancers and presumed rarity in normal tissues. However, recent studies show that positive selection in normal epithelia can increase the prevalence of some cancer drivers. To determine their true cancer-driving potential, it is essential to evaluate how frequent these mutations are in normal tissues and what are their phenotypes. Here, we explore the bioavailability of somatic variants by quantifying age-related mutational burdens in normal human colonic epithelium using immunodetection in FFPE samples (N = 181 patients). Positive selection of variants of tumour suppressor genes PTEN and ARID1A associates with monoallelic gene loss as confirmed by CRISPR/Cas9 mutagenesis and changes in their downstream effectors. Comparison of the mutational burden in normal tissue and colorectal cancers allows quantification of cancer driver potency based on relative representation. Additionally, immune exclusion, a cancer hallmark feature, is observed within ARID1A-deficient clones in histologically normal tissue. The behaviour resulting from haploinsufficiency of PTEN and ARID1A demonstrates how somatic mosaicism of tumour suppressors arises and can predispose to cancer initiation.

Metadata

Item Type:	Article
Authors/Creators:	Skoufou-Papoutsaki, N. Adler, S. Mehmed, S. Tume, C. Olpe, C. Morrissey, E. Kemp, R. Girard, A.-C. Moutin, E.B. Chilamakuri, C.S.R. Miller, J.L. Lindskog, C. Werle, F. Marks, K. https://orcid.org/0000-0003-2753-6238 Perrone, F. Zilbauer, M. Tourigny, D.S. Winton, D.J.
Copyright, Publisher and Additional Information:	© The Author(s). 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/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.
Keywords:	Haploinsufficency; Clone Dynamics; Normal Tissue; PTEN; ARID1A
Dates:	Accepted: 10 January 2025 Published (online): 7 February 2025 Published: March 2025
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 Pathological Society Of Great Britain & Ireland Not Known Cancer Research UK Supplier No: 138573 A28063
Date Deposited:	26 Jun 2026 14:43
Last Modified:	26 Jun 2026 14:43
Status:	Published
Publisher:	Springer Nature
Identification Number:	10.1038/s44319-025-00373-0
Related URLs:	Author Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:242407