Integrated Analysis Identifies Molecular Signatures and Specific Prognostic Factors for Different Gastric Cancer Subtypes1

BACKGROUND Gastric cancer (GC) is the fifth leading cause of cancer-related deaths worldwide. As an effective and easily performed method, microscopy-based Lauren classification has been widely accepted by gastrointestinal surgeons and pathologists for GC subtyping, but molecular characteristics of different Lauren subtypes were poorly revealed. METHODS GSE62254 was used as a derivation cohort, and GSE15459 was used as a validation cohort. The difference between diffuse and intestinal GC on the gene expression level was measured. Gene ontology (GO) enrichment analysis was performed for both subgroups. Hierarchical clustering and heatmap exhibition were also performed. Kaplan-Meier plot and Cox proportional hazards model were used to evaluate survival grouped by the given genes or hierarchical clusters. RESULTS A total of 4598 genes were found differentially expressed between diffuse and intestinal GC. Immunity- and cell adhesion-related GOs were enriched for diffuse GC, whereas DNA repair- and cell cycle-related GOs were enriched for intestinal GC. We proposed a 40-gene signature (χ2=30.71, P<.001) that exhibits better discrimination for prognosis than Lauren classification (χ2=12.11, P=.002). FRZB [RR (95% CI)=1.824 (1.115-2.986), P=.017] and EFEMP1 [RR (95% CI)=1.537 (0.969-2.437), P=.067] were identified as independent prognostic factors only in diffuse GC but not in intestinal GC patients. KRT23 [RR (95% CI)=1.616 (0.938-2.785), P=.083] was identified as an independent prognostic factor only in intestinal GC patients but not in diffuse GC patients. Similar results were achieved in the validation cohort. CONCLUSION We found that GCs with different Lauren classifications had different molecular characteristics and identified FRZB, EFEMP1, and KRT23 as subtype-specific prognostic factors for GC patients.