The somatic mutation landscape of normal gastric epithelium

ABSTRACT 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.