Gene expression data of organoids derived from human gastric tumor and normal stomach samples.. Gene expression data of organoids derived from human gastric tumor and normal stomach samples.

Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers. Overall design: We analyzed gene expression of 36 patient-derived gastric tumor, 9 normal-like, 1 IM, 8 normal stomach, 1 normal colon, 5 engineered normal stmomach and 1 engineered normal colon organoids. mRNA were extracted from organoids and hybridized to GeneChip PrimeView Human Gene Expression Array, and scanned using GeneChip Scanner 3000 7G.