Spatial transcriptomic profiling of signet ring cell precursors of diffuse-type gastric cancer

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. Transcriptomic profiling was performed to establish the molecular phenotype of early SRC lesions. We performed NanoString GeoMx digital spatial profiling (DSP) using the whole transcriptome atlas (WTA) panel to characterize gastric tissue regions of interest (ROIs). Early tumor stage (T1a) gastric epithelial (T1a_NEP) and SRC lesion (T1a_SRC) ROIs were captured from total gastrectomy samples of four patients with germline CDH1 P/LP variants. In four patients with advanced DGC found on gastrectomy explants, ROIs were selected from gastric epithelial (GC_NEP), superficial lamina propria (GC_sup), as well as from submucosa and deeper (GC_deep).