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Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
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DNA Methylation Profiling of Human Hepatocarcinogenesis.
Gabriela Hernandez-Meza1, Johann von Felden1,2, Edgar E Gonzalez-Kozlova3
1Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Hepatology (Baltimore, Md.)
|November 25, 2020
Summary
Epigenetic changes, specifically DNA methylation, track liver cancer development from precancerous stages to early HCC. These methylation patterns in cirrhotic tissue can predict patient survival outcomes.
Area of Science:
- Hepatology
- Epigenetics
- Oncology
Background:
- Telomerase reverse transcriptase (TERT) promoter mutations are known drivers of early liver cancer.
- Epigenetic alterations, particularly DNA methylation, are crucial in early malignancy development.
- Understanding molecular changes beyond TERT mutations is vital for early hepatocarcinogenesis research.
Purpose of the Study:
- To analyze DNA methylation changes during the progression from preneoplastic lesions to early hepatocellular carcinoma (eHCC).
- To identify novel epigenetic gatekeepers involved in hepatocarcinogenesis.
- To evaluate the prognostic significance of DNA methylation alterations in cirrhotic liver tissue.
Main Methods:
- Genome-wide methylome profiling using Illumina HumanMethylation450 array on 390 liver samples (healthy, cirrhotic, dysplastic nodules, HCC).
- Phylo-epigenetic tree construction to visualize methylation gradients across disease stages.
- Analysis of promoter methylation, correlation with gene expression, and unsupervised clustering of cirrhotic tissue methylation profiles.
Main Results:
- DNA methylation profiles effectively differentiate histological stages of liver cancer, showing a gradient from healthy to cirrhotic to dysplastic to HCC.
- Epigenetic gatekeeper candidates identified, with increasing hypermethylation in promoter regions from cirrhotic tissue to dysplastic nodules to eHCC.
- Inverse correlation between DNA methylation and gene expression observed for genes including TSPYL5, KCNA3, LDHB, and SPINT2.
- Two distinct methylation clusters (M1, M2) in cirrhotic tissue correlated with patient survival, independent of liver disease etiology.
Conclusions:
- Genome-wide DNA methylation patterns accurately distinguish histological stages of human hepatocarcinogenesis.
- Epigenetic gatekeepers were identified during the transition from dysplastic nodules to early HCC.
- DNA methylation changes in cirrhotic tissue hold prognostic value for clinical outcomes.
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