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Updated: Jan 31, 2026

Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Characterization and clinical implications of CpG island methylator phenotypes of resistant tumors
Fei Hou1, Xu Zhou1,2, Yu-E Huang3
1Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, 211106, China.
Background:
Drug resistance, characterized by high heterogeneity and complex mechanisms, poses a significant challenge in cancer treatment. Stratifying resistant tumors into biologically and clinically meaningful subgroups can improve prognostic evaluation and help guide treatment decisions. However, the DNA methylation-based subtypes of resistant tumors have not yet been comprehensively characterized.
Results:
DNA methylation profiles from resistant tumors were retrieved from public database including TCGA and GEO. For each tumor type resistant to a specific treatment drug, consensus clustering based on the most variable methylated probes was conducted to identify the DNA methylation subtypes of resistant tumors. For low-grade glioma (LGG) resistant to Temozolomide, consensus clustering of highly variable CpGs identified two subtypes: cancer resistance CpG island methylator phenotype-positive (CR_CIMP+) and -negative (CR_CIMP-). The CR_CIMP- subtype associates with poorer prognosis, reduced drug response, and more advanced histology, exhibiting higher tumor mutation burden and greater activity in drug resistance-related pathways, such as PI3K/AKT/mTOR signaling. CR_CIMP subtypes with distinct clinical or molecular features were also identified in pancreatic adenocarcinoma and bladder urothelial carcinoma resistant to Gemcitabine, as well as in non-small cell lung cancer resistant to anti-PD1/PD-L1 immunotherapy. Based on predicted drug responses, the study screens candidate drugs for each CR_CIMP subtype. Finally, a random forest model is proposed to predict CR_CIMP subtypes in LGG patients resistant to Temozolomide.
Conclusions:
This study uncovers DNA methylation subtypes within resistant tumors, enabling more precise stratification to inform prognosis and therapy selection.
Insights
This study identifies DNA methylation subtypes in drug-resistant cancers, improving prognosis and treatment selection. These subtypes, like CR_CIMP in low-grade glioma, offer new ways to stratify patients for targeted therapies.
Area of Science:
- Cancer Genomics
- Epigenetics
- Computational Biology
Background:
- Drug resistance in cancer presents significant heterogeneity and complexity.
- Stratifying resistant tumors is crucial for prognosis and guiding treatment.
- DNA methylation-based subtypes of resistant tumors remain poorly characterized.
Purpose of the Study:
- To characterize DNA methylation subtypes in various drug-resistant tumors.
- To identify novel molecular subgroups for improved cancer patient stratification.
- To explore potential therapeutic strategies based on identified subtypes.
Main Methods:
- Retrieved DNA methylation profiles from public databases (TCGA, GEO).
- Applied consensus clustering on variable CpGs to identify methylation subtypes.
- Utilized random forest models for subtype prediction in specific cancers.
Main Results:
- Identified two DNA methylation subtypes (CR_CIMP+ and CR_CIMP-) in Temozolomide-resistant low-grade glioma.
- The CR_CIMP- subtype showed poorer prognosis, reduced drug response, and activated resistance pathways.
- Discovered distinct CR_CIMP subtypes in Gemcitabine-resistant pancreatic cancer/bladder cancer and anti-PD1/PD-L1-resistant NSCLC.
Conclusions:
- Uncovered novel DNA methylation subtypes within drug-resistant tumors.
- Enables more precise stratification of resistant tumors for clinical decision-making.
- Provides a foundation for personalized therapy selection in resistant cancers.
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