威康桑格研究所Michael R. Stratton研究团队在研究中取得进展。他们的最新研究报道了正常胃上皮的体细胞突变图。2025年3月19日，国际知名学术期刊《自然》发表了这一成果。

通过对来自30个个体（包括18个胃癌患者）的238个显微解剖标本进行全基因组测序，研究小组阐明了正常和恶性胃上皮的发育轨迹。该团队发现胃腺是单克隆细胞群的单位，每年产生大约28个体细胞单核苷酸变异，主要归因于内源性突变过程。在胃癌患者中，由于与增殖和氧化损伤相关的突变过程加速，化生腺体经常表现出突变负担增加。与正常细胞不同的是，胃上皮细胞经常携带特定染色体的复发三体，这些染色体在一小部分个体中高度富集。通过靶向测序对829例多克隆胃显微活检进行调查，小组发现了已知癌症基因中独特的体细胞“驱动”突变，包括ARID1A、ARID1B、ARID2、CTNNB1和KDM6A。突变克隆的患病率随着年龄的增长而增加，到60岁时约占胃上皮组织的8%，并且由于存在严重的慢性炎症而显着增加。他们的发现提供了对健康、癌前和恶性状态下胃上皮体细胞进化的内在和外在影响的见解。

据悉，正常细胞中体细胞突变的景象告诉他们突变和选择在整个生命中起作用的过程，为正常衰老和癌症发展的早期阶段提供了见解。

附：英文原文

Title: The somatic mutation landscape of normal gastric epithelium

Author: Coorens, Tim H. H., Collord, Grace, Jung, Hyungchul, Wang, Yichen, Moore, Luiza, Hooks, Yvette, Mahbubani, Krishnaa, Law, Simon Y. K., Yan, Helen H. N., Yuen, Siu Tsan, Saeb-Parsy, Kourosh, Campbell, Peter J., Martincorena, Iigo, Leung, Suet Yi, Stratton, Michael R.

Issue&Volume: 2025-03-19

Abstract: The landscapes of somatic mutation in normal cells inform us about the processes of mutation and selection operative throughout life, providing insight into normal ageing and the earliest stages of cancer development1. Here, by whole-genome sequencing of 238 microdissections2 from 30 individuals, including 18 with gastric cancer, we elucidate the developmental trajectories of normal and malignant gastric epithelium. We find that gastric glands are units of monoclonal cell populations that accrue roughly 28 somatic single-nucleotide variants per year, predominantly attributable to endogenous mutational processes. In individuals with gastric cancer, metaplastic glands often show elevated mutation burdens due to acceleration of mutational processes linked to proliferation and oxidative damage. Unusually for normal cells, gastric epithelial cells often carry recurrent trisomies of specific chromosomes, which are highly enriched in a subset of individuals. Surveying 829 polyclonal gastric microbiopsies by targeted sequencing, we find somatic ‘driver’ mutations in a distinctive repertoire of known cancer genes, including ARID1A, ARID1B, ARID2, CTNNB1 and KDM6A. The prevalence of mutant clones increases with age to occupy roughly 8% of the gastric epithelial lining by age 60 years and is significantly increased by the presence of severe chronic inflammation. Our findings provide insights into intrinsic and extrinsic influences on somatic evolution in the gastric epithelium in healthy, precancerous and malignant states.

DOI: 10.1038/s41586-025-08708-6

Source: https://www.nature.com/articles/s41586-025-08708-6