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

Abstract

Hypothesis: Poorly cohesive (PC) gastric cancer (GC) exhibits variable clinical behavior, 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. Materials and Methods: 64 PC GCs were assessed for alterations in 409 genes and 30 cases were subjected to transcriptomic profiling of 20,815 genes. Results: A median of 8.2 mutations per Mb (interquartile range 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 1 chromatin remodeling 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 signaling; 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). Conclusion: 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.

Clinicopathological features and cancer transcriptomic profiling of poorly cohesive gastric carcinoma subtypes

“…Despite refinement of the pathological classification criteria and the distinctively different morphologies, both PCC‐NOS and SRCC are classified under the same molecular subtypes of GC, specifically the genomic stability type in The cancer genome atlas (TCGA) or the microsatellite stable/epithelial‐to‐mesenchymal (EMT) transition type in the Asian Cancer Research Group (ACRG) molecular subgroups [ 13 , 14 ]. Several studies have aimed to further classify PCC into various molecular subtypes, and PCC enriched in immune response proteins and EMT features is associated with a worse outcome [ 15 , 16 ]. Nevertheless, the linkage between PCC morphology and molecular features has been poorly studied.…”

Immunohistochemical Markers of the Epithelial-to-Mesenchymal Transition (EMT) Are Related to Extensive Lymph Nodal Spread, Peritoneal Dissemination, and Poor Prognosis in the Microsatellite-Stable Diffuse Histotype of Gastric Cancer

“…Genomic analyses showed that the signaling pathways of the EMT identify the so-called mesenchymal type of GC, and most of such cases are of diffuse histology [ 16 ]. Interestingly, poorly cohesive GC also showed a worse prognosis when associated with EMT signature [ 17 ]. To date, it is unclear if the association with diffuse histology acts as a confounding factor, or, alternatively, if EMT status could identify a more aggressive phenotype in the context of the diffuse-type group.…”