Aberrant deoxyribonucleic acid methylation in human thyroid tumors.
Aberrant deoxyribonucleic acid methylation in human thyroid tumors.
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DOI：
10.1210/jcem.77.4.7691865
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发表时间：
1993-10
期刊：
影响因子：
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通讯作者：
Keiichi Matsuo;Shih-Huey Tang;Kazuya Zeki;Gutman Ra;J A Fagin
中科院分区：
文献类型：
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作者：
Keiichi Matsuo;Shih-Huey Tang;Kazuya Zeki;Gutman Ra;J A Fagin
DNA 甲基化是脊椎动物中二核苷酸序列 CpG 处发生的胞嘧啶残基的共价修饰。在人类肿瘤中始终观察到 DNA 甲基化的异常模式，包括广泛的基因组低甲基化区域以及区域性高甲基化区域。我们检查了良性和恶性人类甲状腺肿瘤的 DNA，以了解人类 GH、血小板衍生生长因子 B 链和 H-ras 基因甲基化状态的变化。人类 GH 基因在多结节性甲状腺肿 (MNG) 22 个结节中的 6 个 (27%)、33 个滤泡性腺瘤 (FA) 中的 21 个 (64%) 和 16 个乳头状癌 (PC) 中的 10 个 (63%) 中异常甲基化。血小板源性生长因子 B 链在 13 例 MNG 中的 4 例 (31%)、24 例 FA 中的 17 例 (71%) 和 13 例 PC 中的 9 例 (69%) 中也异常甲基化。 H-ras 基因位于染色体 11p 上的一个区域，该区域已知是其他肿瘤类型中高甲基化的热点区域，在 22 个 MNG 中的 6 个 (27%)、35 个 FA 中的 22 个 (63%) FA 和 16 个 PC 中的 10 个 (63%) 中，H-ras 基因显示出复杂的甲基化模式（主要是高甲基化）。那些甲基化异常的肿瘤往往在多个位点受到影响（即所有 3 个探针的异常模式），而那些呈阴性的肿瘤通常在所有位点均正常。良性和恶性甲状腺肿瘤显示选定基因的异常甲基化模式的发生率很高。多结节性甲状腺肿的腺瘤结节主要由增生组织组成，这些事件的发生频率较低。异常的 DNA 甲基化可能通过 DNA 构象、转录活性的变化和/或增加脆弱位点的不稳定性而导致随后的细胞转化。这表明 DNA 甲基化的广泛变化可能是甲状腺肿瘤形成的相对早期步骤。
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.