Clinical behavior of poorly cohesive (PC) gastric cancer (GC) varies widely, ranging from high aggression in most cases to relative passivity in others. Researchers predicted that distinguishing molecular subgroups with possible therapeutic implications could be aided by an integrative genomic and gene expression characterization of a PC GC series. For 64 PC GCs, we analyzed changes in 409 genes, and for 30 instances, they performed transcriptome profiling of 20,815 genes. The median number of mutations per megabase was 8.2 (IQR: 6.9-10.4), and a tumor mutational burden of more than 10 muts/Mb was substantially linked with poorer survival (P=0.0024). CDH1 (32.8%), TP53 (32.8%), and PIK3CA (10.9%) were the genes most commonly altered. Mutations in at least 1 chromatin remodeling gene were found in 15 samples (23.4%); they included KMT2D (5 cases), ARID1A and BAP1 (4 cases each), EZH2, KMT2A, PBRM1, and BAP1 (1 case each). In 8 cases (12.5%), fusion genes were found that involved the CLDN18 gene. Cluster A was associated with an epithelial to mesenchymal transition EMT signature, Cluster B with a proliferative signature and EMT, Cluster C with a correlation to hedgehog signaling, Cluster D with a correlation to hedgehog signaling, and Cluster D with no enrichment for any of the aforementioned signatures. There was a statistically significant difference in outcomes between groups C and D and groups A and B (P=0.0095). EMT characteristics are related to a worse outcome; an integrated genomic and transcriptome study suggests the existence of 4 molecular subtypes of PC GC with prognostic importance.
