An Integrated Multi-Omics and Causal Inference Study Identifies a DNA Repair-Related Prognostic Biomarker in Gastric Cancer.
TL;DR
Findings suggest that BRCA1 is not an independent prognostic factor but reflects broader tumor biological processes, particularly DNA repair and redox regulation, and positioning BRCA1 as a key component of tumor biology and a potential target for precision oncology strategies.
Abstract
Objective
This study aims to identify biologically relevant genes associated with DNA repair pathways in gastric cancer (GC) by integrating multi-omics analyses with causal inference approaches.
Methods
Public GC datasets were integrated to identify consensus differentially expressed genes (DEGs). Candidate genes were screened using WGCNA and intersected with DEGs. Key genes were selected via the machine learning algorithm Lasso+plsRglm and validated by the Area Under the Receiver Operating Characteristic Curve (AUC) analysis. The Protein-Protein Interaction (PPI) network determines the hub genes associated with GC. Single-cell RNA sequencing characterized the cell-type-specific gene expression. Kaplan-Meier analysis assessed the prognostic relevance. Immune infiltration was evaluated using CIBERSORT and ESTIMATE algorithms. Mendelian Randomization (MR) examined causal relationships among BRCA1, NADPH, and GC risk. Experimental validation was performed using qRT-PCR and Western blot in GC cell lines and clinical samples.
Results
Five hub genes, i.e., BRCA1, CCNA2, CHEK1, KIF14, and KIF15, predominantly enriched in mesenchymal stem cells and fibroblasts, were identified. BRCA1 was consistently overexpressed in GC and associated with improved survival and enhanced antitumor immune activity. MR analysis suggested indirect associations between BRCA1, NAD(P)H metabolism, and GC risk, without a direct causal effect. Experimental results confirmed significant overexpression of BRCA1 at both mRNA and protein levels in GC.
Discussion
These findings suggest that BRCA1 is not an independent prognostic factor but reflects broader tumor biological processes, particularly DNA repair and redox regulation. Its upregulation likely represents a compensatory response to genomic instability. The identified BRCA1-NAD(P)H axis highlights a potential mechanistic link between DNA repair and metabolic regulation, underscoring its relevance in tumor progression and therapeutic targeting.
Conclusion
This study reveals a regulatory link between DNA repair, redox metabolism and GC progression, positioning BRCA1 as a key component of tumor biology and a potential target for precision oncology strategies.