Abstract

Abstract Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multi-omics analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of ECM remodeling in SRC lesions compared to unaffected adjacent gastric epithelium. Single cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin re-expression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared to SRC lesions. Implications: The marked differences in genomic and transcriptomic profile of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.