Poorly Cohesive Gastric Cancers Showing the Transcriptomic Hallmarks of Epithelial-Mesenchymal Transition Behave Aggressively.

Poorly cohesive (PC) gastric cancer (GC) exhibits variable clinical behaviour, being extremely aggressive in most cases but more indolent at times. We hypothesized that the integrative genomic and gene expression characterization of a PC GC series could help identifying molecular subtypes with potential clinical implications.64 PC GCs were assessed for alterations in 409 genes and 30 cases were subjected to transcriptomic profiling of 20,815 genes.A median of 8.2 mutations per Mb (IQR 6.9-10.4) was found and a tumor mutational load >10 muts/Mb was significantly associated with patients' worse survival (P=0.0024). The most frequent mutated genes were CDH1 and TP53 (each 32.8%) followed by PIK3CA (10.9%). In 15 samples (23.4%), at least one chromatin remodelling gene was mutated: KMT2D (5 cases); ARID1A and BAP1 (4 cases each); EZH2, KMT2A, PBRM1 (1 case each). Eight samples (12.5%) had fusion genes involving CLDN18 gene. Gene expression profiling identified 4 different clusters: cluster A associated with epithelial to mesenchymal transition (EMT) signature; cluster B associated to proliferative signature and EMT; cluster C correlated to hedgehog signalling; cluster D showing no enrichment for any of the previous signatures. Notably, cluster A and B showed a worse prognosis compared with clusters C and D (P=0.0095).integrated genomic and transcriptomic analysis suggest the existence of 4 molecular subtypes of PC GC with prognostic significance where EMT features are associated with a worse outcome.