Abstract 226: Recurrent trisomies, variable selection and precancerous evolution in the normal gastric epithelium

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Abstract Gastric cancer is the third leading cause of cancer-related mortality globally and is often associated with infectious agents such as the bacterium Helicobacter pylori. However, the background mutational landscape in normal gastric epithelium and the first genomic steps towards the formation of gastric cancer remain poorly understood. Here, we use whole-genome sequencing of microdissected gastric glands (n=271) from 30 patients, 18 of whom had gastric cancer. We show that gastric glands are clonal structures and accrue approximately 27 single base substitutions per year. While the mutational signatures in most normal glands reflect age-related mutagenesis, gastric glands sampled close to a tumor showed exposure to a mutagenic process enriched in tumors (COSMIC reference mutational signature SBS17). Phylogenetic analysis shows that acquisition of SBS17 substitutions is closely linked to overt malignant transformation. We also observe widespread trisomies of specific chromosomes, which are recurrently and independently acquired in many gastric glands of the same patient. Mutations in genes encoding epigenetic modifiers and chromatin remodelers showed evidence of positive selection and were highly enriched in some patients. This was confirmed by targeted sequencing of cancer genes in a further 1008 gastric glands. Strikingly, glands that exhibit driver mutations, a recurrent trisomy or elevated mutation loads only overlap minimally, suggesting a highly variable and patient-specific mutation and selection landscape in the normal gastric epithelium. Taken together, these results give novel insights into the preclinical evolution of gastric malignancies. Citation Format: Tim H. Coorens, Grace Collord, Hyungchul Jung, Yichen Wang, Sonia Zumalave, Daniel Leongamornlert, Luiza Moore, Krishnaa Mahbubani, Kourosh Saeb-Parsy, Suet Yi Leung, Michael R. Stratton. Recurrent trisomies, variable selection and precancerous evolution in the normal gastric epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 226.

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