Molecular features and prognostic factors of locally advanced microsatellite instability-high gastric cancer

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Microsatellite instability-high (MSI-H) tumors represent a distinct molecular subtype of gastric cancer.
• Limited comprehensive data exists on MSI-H tumors in locally advanced gastric cancer regarding molecular features and prognostic factors.

Purpose of the Study:

• To elucidate the molecular characteristics of locally advanced MSI-H gastric cancer.
• To identify prognostic factors influencing survival in this patient group.

Main Methods:

• Analysis of 499 locally advanced gastric cancer patients undergoing radical gastrectomy.
• Evaluation of MSI status and comparison with existing sequencing and gene expression data.
• Comparison of clinicopathological and molecular profiles between MSI-H and microsatellite-stable (MSS) gastric cancer patients.

Main Results:

• MSI-H tumors (15.8%) exhibited increased tumor mutational burden, MLH1 downregulation, PD-L1 upregulation, and cell cycle pathway enrichment.
• Disease-specific survival (DSS) was improved with surgery plus S-1 adjuvant chemotherapy, particularly in stage III MSI-H patients.
• Higher DSS was observed in the T cell-inflamed gene expression signature-high group, while the non-solid type poorly differentiated adenocarcinoma group showed worse DSS.

Conclusions:

• The study clarifies molecular features and prognostic factors for locally advanced MSI-H gastric cancer.
• S-1 adjuvant chemotherapy shows potential benefit.
• T cell-inflamed gene expression signature and histopathological type are significant prognostic factors for MSI-H tumors.