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 singlestrand 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. (J. Clin. Invest. 1993. 91:179-184.)
Structural alterations of protooncogene sequences may be involved in the pathogenesis of human neoplasms. We screened 54 thyroid tumors (36 benign and 18 malignant) for gene rearrangements of the protooncogenes c-myc, c-myb, c-fos, c-erb-B1, c-erb-B2, c-erb-A, N-ras, K-ras, and H-ras. Only mutations of H-ras were observed. None of the 15 colloid adenomas examined had detectable H-ras rearrangements. Of the remaining tumors, we observed mutations of H-ras in 4 benign and 4 malignant neoplasms. Gene amplification was found in 5 tumors. An aggressive recurrent papillary carcinoma had a marked amplification of one of the H-ras alleles. The amplified allele was truncated, in that the 3' variable tandem repeat was not a part of the amplification unit, and contained a codon 12 point mutation leading to a valine for glycine substitution. We also observed the association of low copy gene amplification with a codon 12 valine for glycine mutation in a follicular adenoma. Two tumors contained H-ras EcoRI polymorphisms not present in the DNA of normal thyroid from the same individuals, and one follicular carcinoma showed loss of an H-ras allele. Ras protooncogenes may become transforming by quantitative mutations, leading to increased expression, or qualitative mechanisms, through activating point mutations. Both of these appear to coexist in thyroid neoplasms, and it may be that a combination of both mechanisms is capable of inducing a more complete spectrum of neoplastic phenotypes.
We determined clonality of thyroid tumors from female patients who had restriction fragment length polymorphisms (RFLP) in the X chromosome genes hypoxanthine phosphoribosyltransferase (HPRT) or phosphoglycerate kinase (PGK). We screened normal thyroid tissue from 59 female patients; of the informative cases 14 were heterozygous for a Bgl I site on PGK and 4 were heterozygous for a Bam HI site on HPRT. In monoclonal tumors, one of the polymorphic alleles was selectively digested after additional digestion with Hpa II, a methylation sensitive enzyme, whereas in polyclonal tissue both were decreased to a similar extent. Normal thyroid tissue from all patients showed a polyclonal pattern. Of the 18 tumors studied, 12 were solitary thyroid nodules, and 6 were obtained from multinodular goiters (MNG). The following were monoclonal: 6/6 follicular adenomas, 2/2 follicular carcinomas, and 1/1 anaplastic carcinoma. Two of the three papillary carcinomas showed intermediate patterns, possibly due to contaminating effects of stromal tissue present in most of these neoplasms. Of the six nodules from MNG, four were polyclonal. The two largest gave a distinct monoclonal pattern. Most solitary thyroid tumors are monoclonal, supporting a somatic cell mutation model of thyroid neoplasm formation. Nodules from MNG are largely hyperplastic, although monoclonal neoplasms do occasionally arise within these glands. The specific somatic mutations leading to clonal expansion and determination of tumor phenotype are presently unknown. (J. Clin. Invest. 1990. 86:120-125.) Key words: follicular neoplasm * papillary carcinoma * multinodular goiter * X chromosome inactivationphosphoglycerate kinase * hypoxanthine phosphoribosyltransferase IntroductionIn the United States, clinically apparent thyroid nodules are present in 4-7% of the adult population (1). There is still no consensus as to the best management of these common endocrine tumors. Preoperative diagnostic techniques offer low specificity, which results in a substantial number of unnecessary operations, and in some patients who are inappropriately left untreated. Even after careful histopathological examination of surgical specimens, it can occasionally be problematic to decide whether a particular thyroid nodule is hyperplastic or
Two classes of genes are the targets of mutations involved in human tumorigenesis: oncogenes, the activation of which leads to growth stimulation, and tumor suppressor genes, which become tumorigenic through loss of function, often through allelic deletion. To obtain evidence for a role for tumor suppressor genes in thyroid tumorigenesis, we examined DNA from 80 thyroid neoplasms for loss of heterozygosity in multiple chromosomal loci using 19 polymorphic genomic probes. None of the informative thyroid tumors studied had allelic loss detected with probes for chromosome 2q (D2S44), 3p (D3F15S2, D3S32), 3q (D3S46), 4p (D4S125), 6p (D6S40), 8q (D8S39), 9q (D9S7), 12p (D12S14), 13q (D13S52), 17p (D17S30), or 18q (D18S10). One of eight of the follicular adenomas had a 10q deletion detected with marker D10S15, and one of 26 had a 10q deletion detected with D10S25. One of two of the follicular carcinomas had an 11p deletion in the H-ras locus. The most significant findings were on chromosome 11q13, the site containing the putative gene predisposing to multiple endocrine neoplasia type I. Four of 27 follicular adenomas had loss of heterozygosity for probes in this region. Allelic deletions were detected with the following probes: D11S149, PYGM, D11S146, and INT2. None of 13 informative papillary carcinomas and none of two follicular carcinomas had loss of heterozygosity detectable with these 11q13 markers. Allelic loss is a relatively infrequent event in human thyroid tumors. Deletions of chromosome 11q13 are present in about 14% of follicular, but not papillary, neoplasms.(ABSTRACT TRUNCATED AT 250 WORDS)
The development and progression of thyroid tumors are associated with phenotype-specific mutations of genes involved in growth control. Thyroid cell growth is controlled in part by the interaction of TSH with its receptor, with subsequent activation of the GTP-binding protein and its effector, adenylyl cyclase. The resulting increase in intracellular cAMP stimulates growth in thyrocytes. The TSH receptor (TSH-R) is a seven-transmembrane domain receptor. Intracellular domains of the TSH-R important for signal transduction and which may serve as targets for mutational activation have been defined. In addition, mutations at specific loci of the alpha-subunit of G-protein in human thyroid tumors have been described. We examined 92 benign and malignant neoplastic thyroid tissues for possible mutations of the intracytoplasmic domains of the TSH-R known to be involved in signal transduction and for mutations within the hot spots of Gs alpha. Screening was carried out by single strand conformation polymorphism (TSH-R) or denaturing gradient gel electrophoresis (Gs alpha) of polymerase chain reaction-amplified tumor DNA. No mutations were observed in the cytoplasmic domains of the TSH-R, except for a neutral base substitution in codon 460 (GCG [Ala]-->GCA [Ala]) in 3 tumors, which was also present in constitutional DNA from the affected individuals. A heterozygous mutation of codon 201 of Gs alpha (GGT [Arg]-CAT [His]) was observed in a nodule from an adenomatous goiter. In addition, a codon 227 mutation (CAG [Glu]-CAT [His]) was identified in a follicular adenoma. We conclude that mutational activation of the intracytoplasmatic domains of the TSH-R is not a significant mechanism of thyroid tumorigenesis, whereas putative activating mutations within exons 8 and 9 of Gs alpha occur infrequently in some benign follicular tumors.
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