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Aberrant deoxyribonucleic acid methylation in human thyroid tumors
1Department of Medicine, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles 90048.
Abstract:
DNA methylation is a covalent modification of cytosine residues that occurs at the dinucleotide sequence CpG in vertebrates. Abnormal patterns of DNA methylation are observed consistently in human tumors, including widespread areas of genomic hypomethylation as well as regional sites of hypermethylation. We examined the DNA of benign and malignant human thyroid tumors for changes in the methylation state of the genes for human GH, platelet-derived growth factor B-chain, and H-ras. The human GH gene was aberrantly methylated in 6 of 22 (27%) nodules from multinodular goiters (MNG), 21 of 33 (64%) follicular adenomas (FA), and 10 of 16 (63%) papillary carcinomas (PC). Platelet-derived growth factor B-chain was also abnormally methylated in 4 of 13 (31%) MNG, 17 of 24 (71%) FA, and 9 of 13 (69%) PC. The H-ras gene, located within a region on chromosome 11p known to be a hot spot for hypermethylation in other tumors types, showed complex patterns of methylation (mainly hypermethylation) in 6 of 22 (27%) MNG, 22 of 35 (63%) FA, and 10 of 16 (63%) PC. Those tumors with methylation abnormalities tended to be affected at multiple loci (i.e. aberrant patterns with all 3 probes), whereas those that were negative were usually normal at all sites. Benign and malignant thyroid neoplasms show a high prevalence of aberrant methylation patterns of selected genes. Adenomatous nodules from multinodular goiters, consisting largely of hyperplastic tissue, have a lower frequency of these events. Aberrant DNA methylation may contribute to subsequent cell transformation through changes in DNA conformation, transcriptional activity, and/or increased fragile site instability. This suggests that widespread changes in DNA methylation may occur as a relatively early step in thyroid tumor formation.
Insights
Aberrant DNA methylation is common in benign and malignant thyroid tumors, affecting genes like human GH, PDGFB, and H-ras. These changes may be an early step in thyroid tumor development.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- DNA methylation, a key epigenetic mechanism, involves modifying cytosine residues at CpG sites in vertebrates.
- Aberrant DNA methylation patterns, including hypomethylation and hypermethylation, are hallmarks of human tumors.
- Thyroid neoplasms exhibit diverse methylation profiles, necessitating investigation into specific gene alterations.
Purpose of the Study:
- To investigate aberrant DNA methylation patterns in genes including human GH, platelet-derived growth factor B-chain (PDGFB), and H-ras in benign and malignant human thyroid tumors.
- To determine the prevalence of these methylation changes in different types of thyroid lesions, such as multinodular goiters (MNG), follicular adenomas (FA), and papillary carcinomas (PC).
Main Methods:
- Analysis of DNA methylation status in human thyroid tumor samples (MNG, FA, PC) using gene-specific probes.
- Assessment of methylation in the human GH, PDGFB, and H-ras genes.
- Correlation of methylation abnormalities with tumor type and multiplicity of affected loci.
Main Results:
- Aberrant methylation of the human GH gene was observed in 27% of MNG, 64% of FA, and 63% of PC.
- Abnormal methylation of PDGFB occurred in 31% of MNG, 71% of FA, and 69% of PC.
- The H-ras gene showed complex methylation patterns (primarily hypermethylation) in 27% of MNG, 63% of FA, and 63% of PC. Tumors with methylation abnormalities often displayed changes at multiple gene loci.
Conclusions:
- Benign and malignant thyroid neoplasms exhibit a high frequency of aberrant DNA methylation in selected genes.
- Adenomatous nodules from MNG show a lower prevalence of these aberrant methylation events compared to FA and PC.
- Aberrant DNA methylation is implicated as a potential early event in thyroid tumorigenesis, possibly influencing cell transformation through altered gene expression and genomic stability.