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06:07
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
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Integrated data analysis reveals potential drivers and pathways disrupted by DNA methylation in papillary thyroid
Caroline Moraes Beltrami1, Mariana Bisarro Dos Reis1,2, Mateus Camargo Barros-Filho1
1International Research Center-CIPE-A.C. Camargo Cancer Center and National Institute of Science and Technology in Oncogenomics (INCiTO), São Paulo, Brazil.
Clinical Epigenetics
|May 5, 2017
Summary
DNA methylation loss in non-promoter regions is significant in papillary thyroid carcinoma (PTC), particularly with BRAF mutations. This study identifies novel regulatory mechanisms and potential biomarkers for PTC development.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Papillary thyroid carcinoma (PTC) incidence is rising globally.
- Previous studies on PTC gene expression and DNA methylation have not fully clarified methylation's regulatory role in gene expression.
- Understanding novel regulatory mechanisms beyond promoters and CpG islands is crucial for PTC research.
Purpose of the Study:
- To identify novel genic and intergenic regions involved in DNA methylation in PTC.
- To elucidate the role of DNA methylation in regulating gene expression in PTC.
- To identify molecular drivers and pathways associated with PTC development through integrative analysis.
Main Methods:
- DNA methylation profiling using Illumina HumanMethylation 450K on 41 PTC and adjacent non-neoplastic tissues (NT).
- Integrative and cross-validation analysis with The Cancer Genome Atlas (TCGA) data.
- Pyrosequencing and RT-qPCR for validation of selected gene methylation and expression patterns.
Main Results:
- 4995 methylated probes (88% hypomethylated) and 1446 differentially expressed transcripts identified between PTC and NT.
- Majority of methylation probes were in non-promoter regions, distant from CpG islands (CGI) and enriched in enhancers.
- Integrative analysis revealed 185 and 38 genes with negative and positive DNA methylation-gene expression correlation, respectively, implicating FGF and retinoic acid signaling pathways.
- BRAF V600E mutation (68% of tumors) correlated with higher demethylation.
- Six genes (ERBB3, FGF1, FGFR2, GABRB2, HMGA2, RDH5) showed confirmed altered methylation and expression patterns.
Conclusions:
- DNA methylation loss in non-promoter, enhancer-enriched regions is a significant event in PTC, especially in BRAF V600E-positive tumors.
- Gene body and 3'UTR methylation can influence gene expression, both repressing and inducing it.
- Integrative analysis identified potential drivers and biomarkers for PTC development regulated by DNA methylation.
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