Related Experiment Video
Updated: Feb 3, 2026
Using Human Differentially Expressed Gene Lists to Perform Downstream Pathway Enrichment Analysis and Target Prioritization
Published on: October 3, 2025
Prediction of Target Genes and Pathways Associated With Cetuximab Insensitivity in Colorectal Cancer
Chaoran Yu1,2, Hiju Hong1,2, Jiaoyang Lu1,2
11 Department of General Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Background:
Cetuximab has been regularly added to the treatments for metastatic colorectal cancer worldwide. However, due to its therapeutic insensitivity and underlying mechanisms being largely unknown, the clinical implementation of cetuximab in colorectal cancer remains limited.
Methods:
The gene expression profile GSE56386 was retrieved from the Gene Expression Omnibus database. Differentially expressed genes were identified between cetuximab-responsive patients and nonresponders, annotated by gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and further analyzed by protein-protein interaction networks. The integrative prognostic analysis was based on The Cancer Genome Atlas and PrognoScan.
Results:
1350 differentially expressed genes were identified with 298 upregulated and 1052 downregulated. Epidermis development, the cornified envelope, calcium ion binding, and amoebiasis were enriched in upregulated genes while digestion, the apical part of the cell, the 3',5'-cyclic-adenosine monophosphate phosphodiesterase activity and pancreatic secretion were found enriched in downregulated genes. The top 10 hub genes were identified, including epithermal growth factor, G-protein subunit β 5, G-protein subunit γ 4, fibroblast growth factor 2, B-cell lymphoma protein 2, acetyl-coenzyme A carboxylase β, KIT proto-oncogene receptor tyrosine kinase, adenylate cyclase 4, neuropeptide Y, and neurotensin. The hub genes exhibited distinct correlations in cetuximab-treated and untreated genomic profiles (GSE56386, GSE5851 and GSE82236). The highest correlation was found between B-cell lymphoma protein 2 and acetyl-coenzyme A carboxylase β in GSE56386. The mRNA expression of hub genes was further validated in the genomic profile GSE65021. Furthermore, B-cell lymphoma protein 2 and acetyl-coenzyme A carboxylase β also exhibited highest degrees among the hub genes correlation networks based on The Cancer Genome Atlas. Both B-cell lymphoma and acetyl-coenzyme A carboxylase β were not independent prognostic factors for colorectal cancer in univariate and multivariate Cox analysis. However, integrative survival analysis indicated that B-cell lymphoma protein 2 was associated with favorable prognosis (hazard ratio = 0.62, 95% confidence interval, 0.30-0.95, P = .024).
Discussion:
This in silico analysis provided a feasible and reliable strategy for systematic exploration of insightful target genes, pathways and mechanisms underlying the cetuximab insensitivity in colorectal cancer. B-cell lymphoma protein 2 was associated with favorable prognosis.
Insights
This study explored gene expression in metastatic colorectal cancer patients treated with cetuximab. B-cell lymphoma protein 2 was identified as a potential prognostic marker for favorable outcomes in colorectal cancer.
Area of Science:
- Oncology
- Genomics
- Bioinformatics
Background:
- Cetuximab is used for metastatic colorectal cancer but faces limitations due to therapeutic insensitivity.
- The mechanisms underlying cetuximab resistance in colorectal cancer are not fully understood, hindering its clinical application.
Purpose of the Study:
- To identify differentially expressed genes, pathways, and hub genes associated with cetuximab response in metastatic colorectal cancer.
- To explore the prognostic significance of identified genes in colorectal cancer.
Main Methods:
- Analysis of gene expression profile GSE56386 from the Gene Expression Omnibus database.
- Identification and annotation of differentially expressed genes using gene ontology and pathway analysis.
- Protein-protein interaction network analysis and integrative prognostic analysis using The Cancer Genome Atlas and PrognoScan.
Main Results:
- 1350 differentially expressed genes were identified, with distinct enrichment in upregulated and downregulated genes.
- Top 10 hub genes were identified, including B-cell lymphoma protein 2 and acetyl-coenzyme A carboxylase β.
- B-cell lymphoma protein 2 was associated with a favorable prognosis in colorectal cancer patients (HR = 0.62, P = .024).
Conclusions:
- This in silico analysis offers a strategy to explore mechanisms of cetuximab insensitivity in colorectal cancer.
- B-cell lymphoma protein 2 shows potential as a prognostic biomarker for improved outcomes in colorectal cancer.
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