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

Abstract

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.

HSPB8 promotes cancer cell growth by activating the ERK‑CREB pathway and is indicative of a poor prognosis in gastric cancer patients

“…In our previous study, we conducted a pilot investigation of expression-based GC biomarker screening and found that HSPB8 is a potential biomarker in both diffuse and intestinal GC (26). In the present study, our results indicated that HSPB8 is a proliferation-promoting protein in GC cell lines, which could also aid in the evasion of apoptosis by GC cells.…”

“…However, there are few reports concerning the role of HSPB8 in gastrointestinal cancers. Based on our previous study of the molecular signature of GC subtypes, HSPB8 was found to be involved in both diffuse and intestinal GCs (26). In the present study, we conducted a series of further assays in vitro and in silico to reveal the biological role and potential prognostic value of HSPB8 in GC.…”

Gene regulatory network construction identified NFYA as a diffuse subtype-specific prognostic factor in gastric cancer

“…Therefore, to the best of our knowledge, more molecular biological studies are based on the Lauren classification system compared with other classification systems, such as the WHO system ( 10 - 15 ). Molecular characteristics at the gene expression level in DF and IT GC have been well identified ( 11 , 12 , 14 , 16 ); however, the gene regulatory networks that distinguish between DF and IT GC remain incompletely characterized.…”

Identification of a novel gene pairs signature in the prognosis of gastric cancer

“…The availability of large‐scale gene expression profiles brings the chance to identify more reliable prognostic signatures in various cancers. Several studies have proposed gene‐expression prognostic signatures in GC . However, the models based on gene expression levels of one dataset were difficult to apply in another dataset directly, considering batch effects .…”