ISSN:1663-2818    

DOI:10.1159/000185454

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:1663-2818    

DOI:10.1159/000185455

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

We have developed mouse models for tumors affecting the epithelial cellular compartment of the thyroid which has been targeted using the bovine thyroglobulin (bTg) promoter. Transgenic mice expressing the human activated c-Ha-Rαs gene developed papillary thyroid carcinomas demonstrating the oncogenic potential of activated Ras gene in the thyroid gland. Transgenic mice express the mutant form of the α subunit of the adenylate cyclase-coupled Gαs with mutations at codon 201 (R201H). The expression of this mutant transgene is not by itself sufficient to produce benign tumors or even hyperplasia, but the transgenic mice have inherited a predisposition to develop thyroid adenom

ISSN:1663-2818    

DOI:10.1159/000185456

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

A point mutation in the protein kinase Cα (PKCα) gene has been discovered in a subpopulation of human pituitary tumors characterized by their invasive phenotype. Here we show that: (1) thyroid tumors can express the PKCα mutation detected in a subpopulation of follicular adenomas and carcinomas, and (2) mutated PKCα has modified enzymatic properties as compared to wild-type PKCα. It has lost its capacity to phosphorylate the S17R substrate and exhibits a higher sensitivity to degradation as compared to wild-type PKCα. In conclusion, the presence of the PKCα mutant in tumors other than pituitary tumors and the observation that the presence of the point mutation induces changes in PKCα properties suggest the involvement of this mutant in tumori

ISSN:1663-2818    

DOI:10.1159/000185457

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Tumours of the thyroid follicular cell are proving to be one of the most informative models for ‘dissecting’ the molecular genetics of multi-stage human tumorigenesis. Early thyroid tumour development is closely correlated with mutation of five alternative genes, ras, ret, trk, gsp and the TSH receptor, associated with different tumour phenotypes, providing an excellent example of genotype/phenotype correlation. For two of these genes, ras and ret, there is also direct experimental evidence from gene transfer studies that they are sufficient to initiate tumorigenesis, one of very few situations where such proof of causality has been obtained for a human tumour. Much less is known of the molecular basis of malignant transformation in thyroid. However, the rare, further progression to undifferentiated (anaplastic) cancer provides a particularly clear-cut illustration of the role of the tumour-suppressor gene p53 in human cancer. Furthermore, in vitro data suggest the intriguing possibility that the anaplastic phenotype results from a combination of p53 mutation together with a spontaneous switch in differentiation programme, i.e. co-operation between a genetic and an epigenetic ev

ISSN:1663-2818    

DOI:10.1159/000185458

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Activating mutations of TSH-R have been described in toxic nodules and more recently in familial nonautoimmune thyrotoxicosis. This last entity is still confused with familial Graves’ disease and the aim of this study is to define its phenotype. Based on 49 patients coming from our first family and on the 4 other kindreds secondarily described in the literature, the phenotypic expression is: a high incidence of hyperthyroidism, an early onset of disease, a higher men/women ratio (17/32) than in Graves’ disease, the absence of ophthalmopathy and of circulating and intrathyroid signs of immunity, a pathology similar to toxic nodule, the need for a total destruction of thyroid tissue to cure the patients. The total analogy with toxic nodule leads us to name this new entity ‘toxic hyperplasia’. Among 92 successive diffuse nonfamilial thyrotoxicosis cases (initially considered as Graves) we isolated 5 cases without extra- and intrathyroidal autoimmunity, raising the question of the existence of an apparent ‘sporadic’ form of toxic hyperplasia (ne

ISSN:1663-2818    

DOI:10.1159/000185459

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The present article reviews the clinical trials that have been performed in recurrent medullary thyroid carcinoma patients with the Affinity Enhancement System. This technique uses bispecific antibodies to target radiolabelled bivalent haptens to tumour cells. Its sensitivity in the detection of known tumour sites is high (90%) and this technique also achieves good sensitivity (61 %) in the detection of occult disease as revealed by abnormal thyrocalciton in blood levels. Due to its high targeting capacity, this technique is now considered for use as a therapeutic agent in medullary thyroid carcinoma patients.

ISSN:1663-2818    

DOI:10.1159/000185460

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Multiple endocrine neoplasia type 2 (MEN-2) is a familial cancer syndrome inherited in an autosomal dominant fashion with age-related penetrance. The main tumour type present in all manifestations of this syndrome, MEN-2A, MEN-2B and familial medullary thyroid carcinoma (FMTC), is medullary thyroid carcinoma (MTC). MTC arises from the parafoUicular or C cells of the thyroid. MEN-2A is characterised by the triad of MTC, phaeochromocytoma, and parathyroid hyperplasia. MEN-2B is characterised by features similar to those of MEN-2A, except for the absence of clinically apparent parathyroid hyperplasia, and additional stigmata including a marfanoid habitus, mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract. FMTC families have MTC as their only phenotype. Missense mutations affecting conserved cysteine codons adjacent to the transmembrane domain of the RET proto-oncogene have been identified in the germline DNA of patients with MEN-2A and FMTC. A single mutation at codon 918 in the tyrosine kinase domain of the RET receptor has been associated with the MEN-2B phenotype. In a small number of FMTC families, missense point mutations have also been identified in the intracellular domain of the RET protein. RET mutation analysis of MEN-2 families has allowed the identification of genotype-pheno-type correlations. While 25% of all MTCs are hereditary, the great majority of MTCs, 75%, are sporadic. Various somatic RET mutations have been identified in sporadic MTCs. In a small number of hereditary MTCs with germline mutations in RET, an additional somatic missense RET mutation has been identified. The discovery of RET mutations in MEN-2 has made possible accurate DNA-based diagnosis and predictive testing. The clinical significance of somatic RET mutations has yet to be determined.

ISSN:1663-2818    

DOI:10.1159/000185461

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Multiple endocrine neoplasia type 1 (MEN-1) is characterized by primary hyperparathyroidism, endocrine pancreatic-duodenal and anterior pituitary tumors. The diagnosis is challenging and involves the exclusion of other endocrine neoplasia syndromes with overlapping features. The predisposing genetic defect was assigned to chromosomal region 11q13 based on linkage analysis. Combined tumor and pedigree genotype analysis showed that allele losses in pancreatic, parathyroid and pituitary tumors eliminated the wild-type allele at the 11q13 loci, suggesting inactivation of a tumor suppressor gene in this region. A 5-Mb integrated map of the region has been established by the European consortium on MEN-1. Based on this mapping the critical interval was restricted to 2 Mb, a region within which eight candidate genes are located.

ISSN:1663-2818    

DOI:10.1159/000185462

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Abnormal cell proliferation is controlled by opposing actions of oncogene products (stimulatory) and tumour suppressor gene (TSG) products (inhibitory). The former are dominantly acting, i.e. only one copy needed for tumorigenesis, whilst for TSG both copies of the gene must be inactivated so these are recessive at a cellular level. For anterior pituitary tumours only one oncogene (Gsp) has been identified in a variable proportion (4-40%) of a single tumour subtype (somatotrophinomas). Contrariwise, allelic deletion studies, using a PCR-based microsatellite polymorphism analysis of DNA extracted from archival specimens, have shown significant loss of heterozygosity in 20-40 % of all tumour subtypes at the locus of the putative MEN-1 gene (chr. 11q13); the retinoblastoma gene (chr. 13q 12-14), and 10q26. Moreover, these DNA microdeletions were concentrated in radiologically invasive tumours compared to noninvasive tumours (modified Hardy gdes 3 and 4 vs. 1+2). In addition, 50% of Cushing’s adenomas showed presence of p53 immunopositivity, though no point mutations in exons 4-9 were found, by SSCP analysis, to account for this. These studies show that analysis of TSGs in pituitary adenomas may provide clues to their pathogenesis, and more importantly relate to clinical behaviour of the tumour, and hence aid decisions regarding managemen

ISSN:1663-2818    

DOI:10.1159/000185463

出版商:S. Karger AG    

年代:1997

数据来源: Karger