Diffuse Gastric Cancer: A Comprehensive Review of Molecular Features and Emerging Therapeutics

Area of Science:

• Oncology
• Molecular Biology
• Gastroenterology

Background:

• Diffuse-type gastric cancer (DGC) represents a significant portion of gastric cancer diagnoses and exhibits aggressive clinical behavior, including peritoneal metastasis and poorer survival rates compared to intestinal-type gastric cancer (IGC).
• Historically, the pathogenesis of DGC has been poorly understood, but recent multiomic studies have begun to elucidate its distinct molecular characteristics.

Purpose of the Study:

• To summarize the unique molecular features of DGC and discuss emerging targeted therapies.
• To highlight advancements in preclinical models and clinical trials for DGC treatment.

Main Methods:

• Review of multiomic studies, including The Cancer Genome Atlas (TCGA) data, to identify molecular subtypes of gastric adenocarcinoma.
• Analysis of preclinical models and clinical trial data for DGC-specific therapies.

Main Results:

• DGC is characterized by specific molecular alterations, including CDH1 mutations, RHOA alterations, and CLDN18-ARHGAP26 fusions.
• Emerging therapies targeting Claudin 18.2 and FGFR2b demonstrate potential, as these biomarkers are enriched in DGC populations.
• Preclinical research indicates therapeutic vulnerabilities in focal adhesion kinase (FAK) and Hippo pathways within DGC models.

Conclusions:

• Recent molecular characterization and targeted therapy development offer a promising outlook for improving DGC patient outcomes.
• Claudin 18.2 and FGFR2b-directed therapies, along with targeting FAK and Hippo pathways, represent key future directions in DGC treatment.