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

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-07 DOI:10.1038/s44319-025-00373-0

Nefeli Skoufou-Papoutsaki, Sam Adler, Shenay Mehmed, Claire Tume, Cora Olpe, Edward Morrissey, Richard Kemp, Anne-Claire Girard, Elisa B Moutin, Chandra Sekhar Reddy Chilamakuri, Jodi L Miller, Cecilia Lindskog, Fabian Werle, Kate Marks, Francesca Perrone, Matthias Zilbauer, David S Tourigny, Douglas J Winton

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引用次数: 0

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.

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.