Diffuse subtype-specific gastric carcinogenesis associated with dysregulation of Notch signaling pathways

Abstract

Gastric tumors are the third leading cause of cancer-related mortality worldwide. This study investigates the effects of Notch signaling pathway dysregulations during gastric carcinogenesis. Hence, the signatures relevant to Notch signaling pathways were collected from the molecular signatures database, and their expression patterns in available mRNA expression profiles of gastric cancer cohorts were explored using a Z score-based pathway activation scoring method. The results of this study uncover that the Notch signaling pathway signatures are dysregulated highly in diffuse subtype-specific gastric cancer rather than intestinal subtype tumors. In addition, ontological functional analysis reveals that Notch signaling involves extracellular matrix structure and complex organization, collagen structure and trimer biosynthesis during their proliferation, survival, and metastasis. The identified pathway dysregulation is further reconfirmed by examining ROC curves of Notch receptor isoform genes such as NOTCH1, NOTCH2, NOTCH3, and NOTCH4, which could prognostic the diffuse subtype-specific gastric tumors with better specificity and sensitivity with greater areas under the curve (AUC) values. Additionally, overall survival (OS) studies also reassured that these gene expressions reveal poor survival patterns associated with highly expressed conditions in diffuse subtypes of gastric cancer patients with significant p-values (p < 0.05). The results of the genomics drug sensitivity in cancer (GDSC) profile show that ERK and MAPK inhibitors are prominent drug targets for this signaling pathway dysregulations in the corresponding subtype of gastric tumors. Thus, the current findings would benefit the development of drug treatments in diffuse subtype-specific gastric carcinogenesis.

Keywords

Gastric cancer / Diffuse subtype / Intestinal subtype / Notch signaling

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