Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer

Abstract

Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-κB, and Wnt/β-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.

LncRNA GClnc1 Promotes Gastric Carcinogenesis and May Act as a Modular Scaffold of WDR5 and KAT2A Complexes to Specify the Histone Modification Pattern

“…Multiple oncogenic pathways may contribute to gastric cancer carcinogenesis ( 40,41 ); however, the potential involvement of lncRNAs is poorly defi ned in human gastric cancer. Through a combination of genomic, biochemical, and cell-biological analyses, we have demonstrated that GClnc1 is a novel oncogenic lncRNA in gastric cancer.…”

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

“…The subsequent activation of Wnt/β-catenin signaling pathway is common in majority of gastric cancers (43). CLDN1 is a known target of β-catenin/TCF/LEF-dependent transcription regulation (28).…”

The Pathogenesis of Gastric Carcinoma

“…The clinical indications to support this hypothesis include the suggestions that (a) proximal gastric tumours have a worse prognosis stage for stage when compared to distal tumours (84), (b) Lauren's diffuse gastric cancers appear to have a different pattern of spread and behaviour than intestinal gastric adenocarcinoma (85), and (c) Her-2 over expression incidence is different between intestinal and diffuse types of gastric cancer. Her2 amplification is most prevalent in proximal or GOJ gastric cancer (30% Her-2 positivity rate) and least prevalent in diffuse type gastric cancer (5% Her2 positivity rate) (86). The RAS pathway seems to be down regulated in proximal non-diffuse gastric cancer when compared with diffuse gastric cancer (87,88).…”