HIGH PREVALENCE OF MUTATIONS OF THE P53 GENE IN POORLY DIFFERENTIATED HUMAN THYROID CARCINOMAS
HIGH PREVALENCE OF MUTATIONS OF THE P53 GENE IN POORLY DIFFERENTIATED HUMAN THYROID CARCINOMAS
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DOI：
10.1172/jci116168
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发表时间：
1993-01-01
影响因子：
15.9
通讯作者：
KOEFFLER, HP
中科院分区：
文献类型：
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作者：
FAGIN, JA;MATSUO, K;KOEFFLER, HP
甲状腺肿瘤的发展和进展是由参与生长控制的基因的表型特异性突变发出信号的。与未分化甲状腺癌相关的分子事件尚不清楚。我们检测了正常、良性和恶性甲状腺组织中p53肿瘤抑制基因的结构异常。通过PCR扩增DNA的单链构象多态性检测突变，使用引物包围外显子5、6、7或8上的已知热点。突变的发生率如下：正常甲状腺0/6;滤泡性腺瘤0/31;乳头状癌0/37;髓样癌0/2;滤泡性癌1 /11;未分化癌5/6;甲状腺癌细胞系3/4。通过PCR产物的直接测序证实阳性病例。所有五个未分化癌组织和未分化癌细胞系ARO具有G：C至A：T的转换，导致密码子273处的Arg至His取代。在肿瘤和细胞系中，鉴定了杂合和纯合p53突变的实例。唯一的甲状腺癌细胞系，其中p53突变没有检测到外显子5-8有显着降低p53 mRNA水平，这表明存在的结构异常的p53本身或一些因素控制其表达。p53突变几乎只存在于低分化甲状腺肿瘤和甲状腺癌细胞系中，这表明p53的失活可能赋予这些肿瘤侵袭性，并进一步丧失分化功能。
The development and progression of thyroid tumors is signaled by phenotype-specific mutations of genes involved in growth control. Molecular events associated with undifferentiated thyroid cancer are not known. We examined normal, benign, and malignant thyroid tissue for structural abnormalities of the p53 tumor suppressor gene. Mutations were detected by single-strand conformation polymorphisms of PCR-amplified DNA, using primers bracketing the known hot spots on either exons 5,6,7, or 8. The prevalence of mutations was as follows: normal thyroid 0/6; follicular adenomas 0/31; papillary carcinomas 0/37; medullary carcinomas 0/2; follicular carcinomas 1 /11; anaplastic carcinomas 5/6; thyroid carcinoma cell lines 3/4. Positive cases were confirmed by direct sequencing of the PCR products. All five anaplastic carcinoma tissues and the anaplastic carcinoma cell line ARO had G:C to A:T transitions leading to an Arg to His substitution at codon 273. In both tumors and cell lines, examples of heterozygous and homozygous p53 mutations were identified. The only thyroid carcinoma cell line in which p53 mutations were not detected in exons 5-8 had markedly decreased p53 mRNA levels, suggesting the presence of a structural abnormality of either p53 itself or of some factor controlling its expression. The presence of p53 mutations almost exclusively in poorly differentiated thyroid tumors and thyroid cancer cell lines suggests that inactivation of p53 may confer these neoplasms with aggressive properties, and further loss of differentiated function.