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Systematic Screening via WGCNA, Machine Learning, and Validation Identifies C3 and CFD as Prognostically Significant
Yuxuan Ma1,2, Xin Liu1,2, Yuhao Wang1,2
1Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Molecular and Cellular Biology
|February 25, 2026
Summary
Key genes C3 and complement factor D (CFD) were identified as crucial tumor suppressors in gastrointestinal stromal tumors (GIST). Their downregulation in GIST correlates with disease progression and poor survival, offering new diagnostic and therapeutic targets.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Gastrointestinal stromal tumors (GIST) are the most common gastrointestinal mesenchymal neoplasms.
- Molecular understanding of GIST is limited, hindering precise diagnosis and targeted therapy.
Purpose of the Study:
- To systematically identify key GIST-associated genes using multiomic integration and experimental validation.
- To establish novel diagnostic biomarkers and therapeutic targets for GIST.
Main Methods:
- Analysis of three GIST transcriptomic datasets with batch effect correction (SVA).
- Identification of differentially expressed genes (DEGs) using limma.
- Prioritization of key genes (C3, CFD) using WGCNA, random forests, and LASSO regression.
- Experimental validation including functional assays and immune infiltration analysis (CIBERSORT, ssGSEA/GSEA).
Main Results:
- Identified 61 DEGs, prioritizing C3 and complement factor D (CFD) with high diagnostic performance (AUCs 0.928 and 0.955).
- Confirmed C3/CFD downregulation in GIST tissues, associated with advanced stage and poor survival.
- Demonstrated tumor-suppressive roles of C3/CFD in inhibiting GIST cell proliferation, colony formation, and migration.
- Linked C3/CFD to altered immune infiltration and metabolic pathways (lipid metabolism, oxidative phosphorylation).
Conclusions:
- C3 and CFD are critical tumor-suppressive biomarkers in GIST.
- These genes modulate immune response and reprogram tumor metabolism.
- C3 and CFD offer promising avenues for GIST diagnosis and targeted therapy.
