Project 1 - Molecular and Cellular Determinants of High Risk Gastric Precancerous Lesions

摘要-项目1 项目1的主要目的是解卷积高危胃癌前体的分子特征， 病变项目负责人Hanlee Ji博士先前发现，早期胃癌的上皮细胞具有以下特征： 通过不同的基因组、转录组和细胞特性。此外，季氏集团还发现了一种独特的基因， 与低风险病变相比，与高风险癌前病变相关的表达谱， 正常对照者项目1是这项工作的继续，具体侧重于描述 胃癌前组织的遗传和分子特征。该项目有两个具体目标： (1)确定与高危胃肠道化生相关的特定基因表达特征 （GIM）。 (2)描述高危胃癌前体中异常上皮细胞及其亚型的特征。 在目标1中，Ji博士将采用批量RNA测序和空间转录组学来研究GIM病变， 在肿瘤进展的范围内。幽门螺杆菌感染状态将被用作分层的危险因素。这些 结果将确定与胃癌和Hp进展的最高风险相关的分子谱， 胃细胞的相关改变。目标2将使用单细胞多组学来鉴定GIM的亚群 上皮细胞的体细胞突变，拷贝数改变和表观遗传模式， 胃癌结果将确定上皮细胞的遗传和基因组特征，这些上皮细胞包含高水平的 胃癌前病变的风险。最终，这个项目将阐明精确的分子和细胞 与高风险GIM相关的特征，以获得对分子，细胞和基因组因素的新见解， 会导致高风险的癌前状态

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.