ABSTRACT – PROJECT 1 The main objective of Project 1 is to deconvolute the molecular features of high-risk gastric cancer precursor lesions. Dr. Hanlee Ji, Project Leader, previously found that the epithelium of early gastric cancer is characterized by distinct genomic, transcriptomic and cellular properties. In addition, the Ji Group has identified a distinct gene expression profile associated with high-risk precancerous gastric lesions compared to low-risk lesions and normal controls. Project 1 represents a continuation of this work with a specific focus on characterizing the genetic and molecular profile of precancerous gastric tissue. There are two specific aims to this project: (1) Identify the specific gene expression signatures associated with high-risk gastric intestinal metaplasia (GIM). (2) Characterize aberrant epithelial cells and their subtypes in high-risk gastric cancer precursors. In Aim 1, Dr. Ji will employ bulk RNA sequencing and spatial transcriptomics to study GIM lesions that range across the spectrum of neoplastic progression. Hp infection status will be used as a stratifying risk factor. These results will identify the molecular profile associated with the highest risk of progression to gastric cancer and Hp- associated alterations in stomach cells. Aim 2 will use single cell multi-omics to identify the subset of GIM epithelial cells with somatic mutations, copy number alterations and epigenetic patterns that are associate with gastric cancer. The results will determine the genetic and genomic features of epithelial cells that comprise high- risk precancerous lesions in the stomach. Ultimately, this project will elucidate the precise molecular and cellular features associated with high-risk GIM to gain novel insight into the molecular, cellular and genomic factors that contribute to a high-risk premalignant state.