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Updated: Jan 12, 2026

Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Integrative methylation and transcriptomic analysis reveals key genes linking cellular senescence and metabolic
Xiaochen Ma1, Lu Chen2, Chenhe Yi1
1Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China.
Abstract:
Colorectal liver metastasis (CRLM) remains lethal, and the convergence of cellular senescence with metabolic reprogramming via epigenomic rewiring is poorly understood. We integrated genome-wide DNA methylation and RNA-seq data from 10 paired primary tumors and liver metastases (GSE213402). After calling differentially methylated genes (3,399 hyper- and 9,519 hypomethylated) and differentially expressed genes (406 DEGs), we intersected them with curated senescence (n = 866) and metabolic reprogramming (n = 948) gene sets, yielding 28 differentially expressed cellular-senescence-related genes (DE-CSRGs) and 24 metabolic-reprogramming-related genes (DE-MRRGs). Machine-learning pipelines (LASSO + SVM-RFE) converged on a five-gene signature: CXCL1, SERPINE1, NDRG1, SRM and GATM, most of which are hypomethylated and over-expressed in metastases. Gene-set enrichment analysis revealed that these genes are involved in pathways such as oxidative phosphorylation, focal adhesion, complement-coagulation cascades, and PPAR signaling. Immune de-convolution revealed strong positive correlations between signature genes and immunosuppressive subsets (MDSCs, Tregs, type-1 T-helper cells; p < 0.05). Elevated IC50 values for oxaliplatin and 5-fluorouracil in metastatic samples were positively associated with NDRG1 and negatively with SRM, indicating chemo-resistance modulation. This five-gene epigenetic-transcriptomic hub identifies a molecular signature that warrants prospective validation as a potential biomarker for patient stratification and combination therapy in CRLM.
Insights
This study uncovers a five-gene signature linking epigenomic changes to cellular senescence and metabolic reprogramming in colorectal liver metastasis (CRLM). This molecular hub may serve as a biomarker for patient stratification and targeted therapies.
Area of Science:
- Oncology
- Genomics
- Epigenetics
Background:
- Colorectal liver metastasis (CRLM) is a significant cause of cancer mortality.
- The interplay between cellular senescence, metabolic reprogramming, and epigenomic alterations in CRLM is not well understood.
Purpose of the Study:
- To identify key genes and pathways involved in the epigenomic rewiring of CRLM.
- To discover a molecular signature for potential use in patient stratification and therapeutic strategies.
Main Methods:
- Integrated genome-wide DNA methylation and RNA-seq data from paired primary tumors and liver metastases.
- Applied machine learning (LASSO + SVM-RFE) to identify a gene signature.
- Performed gene-set enrichment and immune deconvolution analyses.
Main Results:
- Identified a five-gene signature (CXCL1, SERPINE1, NDRG1, SRM, GATM) associated with CRLM, characterized by hypomethylation and overexpression.
- These genes are implicated in pathways like oxidative phosphorylation and focal adhesion.
- Signature genes correlated with immunosuppressive immune cells and modulated chemo-resistance.
Conclusions:
- A five-gene epigenetic-transcriptomic signature is identified in colorectal liver metastasis.
- This signature holds potential as a biomarker for patient stratification and combination therapy development.
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