An Integrated Multi-Omics and Causal Inference Study Identifies a DNA Repair-Related Prognostic Biomarker in Gastric...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Gastric cancer (GC) remains a significant global health challenge.
• Understanding the molecular mechanisms driving GC progression is crucial for developing effective therapies.

Purpose of the Study:

• To identify biologically relevant genes in DNA repair pathways in GC using multi-omics and causal inference.
• To elucidate the role of key genes, such as BRCA1, in GC pathogenesis and their association with metabolic regulation.

Main Methods:

• Integration of public GC datasets to identify differentially expressed genes (DEGs).
• Weighted Gene Co-expression Network Analysis (WGCNA), machine learning (Lasso+plsRglm), and Protein-Protein Interaction (PPI) networks to identify hub genes.
• Single-cell RNA sequencing, Mendelian Randomization (MR), Kaplan-Meier analysis, and immune infiltration analysis.
• Experimental validation using qRT-PCR and Western blot.

Main Results:

• Five hub genes, including BRCA1, were identified, enriched in mesenchymal stem cells and fibroblasts.
• BRCA1 was consistently overexpressed in GC, correlating with improved survival and enhanced antitumor immunity.
• Mendelian Randomization suggested indirect associations between BRCA1, NAD(P)H metabolism, and GC risk, with experimental validation confirming BRCA1 overexpression.

Conclusions:

• BRCA1 is implicated in broader tumor biological processes, including DNA repair and redox regulation, rather than being an independent prognostic factor.
• The identified BRCA1-NAD(P)H axis highlights a link between DNA repair and metabolic regulation in GC progression.
• BRCA1 represents a potential target for precision oncology strategies in gastric cancer.