The somatic mutation landscape of normal gastric epithelium

体细胞 生物 癌症 ARID1A型 癌症的体细胞进化 肠化生 突变 上皮 化生 种系突变 癌症研究 遗传学 病理 基因 医学
作者
Tim Coorens,Grace Collord,Hyungchul Jung,Yichen Wang,Luiza Moore,Yvette Hooks,Krishnaa T. Mahbubani,Kourosh Saeb‐Parsy,Peter J. Campbell,Iñigo Martincorena,Suet Yi Leung,Michael R. Stratton
标识
DOI:10.1101/2024.03.17.585238
摘要

The landscapes of somatic mutation in normal cells inform on the processes of mutation and selection operative throughout life, permitting insight into normal ageing and the earliest stages of cancer development. Here, by whole-genome sequencing of 238 microdissections 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 which accrue ~28 somatic single nucleotide variants per year, predominantly attributable to endogenous mutational processes. In individuals with gastric cancer, glands often show elevated mutation burdens due to acceleration of mutational processes linked to proliferation and oxidative damage. These hypermutant glands were primarily detected in the gastric antrum and were mostly associated with chronic inflammation and intestinal metaplasia, known cancer risk factors. Unusually for normal cells, gastric epithelial cells often carry recurrent trisomies of specific chromosomes, which are highly enriched in a subset of individuals. Surveying approximately 8,000 gastric glands by targeted sequencing, we found somatic driver mutations in a distinctive repertoire of known cancer genes, including ARID1A, CTNNB1, KDM6A and ARID1B. Their prevalence increases with age to occupy approximately 5% of the gastric epithelial lining by age 60 years. Our findings provide insights into the intrinsic and extrinsic influences on somatic evolution in the gastric epithelium, in healthy, precancerous and malignant states.
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