Aberrant deoxyribonucleic acid methylation in human thyroid tumors.

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.