Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tall-cell variant (TCV) of papillary thyroid carcinoma (PTC), characterized by tall cells bearing an oxyphilic cytoplasm, is more clinically aggressive than conventional PTC. RET tyrosine kinase rearrangements, which represent the most frequent genetic alteration in PTC, lead to the recombination of RET with heterologous genes to generate chimeric RET/PTC oncogenes. RET/PTC1 and RET/PTC3 are the most prevalent variants. We have found RET rearrangements in 35.8% of TCV (14 of 39 cases). Whereas the prevalences of RET/PTC1 and RET/PTC3 were almost equal in classic and follicular PTC, all of the TCV-positive cases expressed the RET/PTC3 rearrangement. These findings prompted us to compare RET/PTC3 and RET/PTC1 in an in vitro thyroid model system. We have expressed the two oncogenes in PC Cl 3 rat thyroid epithelial cells and found that RET/PTC3 is endowed with a strikingly more potent mitogenic effect than RET/PTC1. Mechanistically, this difference correlated with an increased signaling activity of RET/PTC3. In conclusion, we postulate that the correlation between the RET/PTC rearrangement type and the aggressiveness of human PTC is related to the efficiency with which the oncogene subtype delivers mitogenic signals to thyroid cells.
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PMID:Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. 1178 18

Hurthle cell adenomas and carcinomas, characterized by the presence of oncocytic cells, are unusual thyroid neoplasms, the treatment of which is still controversial. We analyzed specimens from 49 patients with oncocytic cell nodular lesions including 20 adenomas, 19 carcinomas, and 10 hyperplasias for RET/PTC (papillary thyroid carcinoma) activation, which is the most frequent genetic alteration in PTCs. RET/PTC activation was detected in a significant number of cases of Hurthle cell adenomas and carcinomas, but in 0 of 10 patients with hyperplastic nodules. In particular, the RET/PTC1 isoform was found in 7 of 12 adenomas and 4 of 7 carcinomas. These results would indicate that RET/PTC is a genetic event common to papillary carcinomas and to Hurthle cell neoplasias.
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PMID:The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hurthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. 1178 77

Poorly differentiated carcinoma of the thyroid gland (PDC) represents an heterogeneous group of epithelial neoplasms with morphologic features and clinical characteristics intermediate between well differentiated and anaplastic (undifferentiated) carcinomas. Unlike well differentiated tumors, PDCs are associated with significant morbidity and mortality. The general prevalence of RET/PTC rearrangement in thyroid PDC and its impact on patient outcome are unknown. To address these issues and to identify prognostically relevant clinicopathologic parameters, we have investigated a series of 62 PDCs. RET/PTC rearrangement, analyzed by RT-PCR and immunohistochemistry using antibodies specific for the tyrosine kinase and juxtamembrane portions of the RET protein, was identified in 8/62 (12.9%) PDCs. RET/PTC was more common in cases with histologic evidence indicating coexistence with or possible evolution from a well differentiated papillary carcinoma (5 of 25 tumors, 20%) but did not correlate with other clinicopathologic parameters. The relatively low prevalence of RET activation in PDCs argues against a major role for RET/PTC in the progression from well to poorly differentiated thyroid tumor phenotypes. Survival analysis demonstrates that poor survival in PDC is associated with old age, male sex, invasion of extrathyroidal soft tissues, coexistence in the same tumor of oncocytic features with insular growth pattern, and distant metastases but not RET activation.
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PMID:RET activation and clinicopathologic features in poorly differentiated thyroid tumors. 1178 78

A novel human thyroid papillary carcinoma cell line (FB-2) has been established and characterized. FB-2 cells harbor the RET/PTC1 chimeric oncogene in which the RET kinase domain is fused to the H4 gene. FB-2 cells neither formed colonies in semisolid media nor induced tumors after heterotransplant into severe combined immunodeficient mice. However, HMGI(Y), HMGI-C and c-myc genes, which are associated to thyroid cell transformation, were abundantly expressed in FB-2 cells but not in normal thyroid cells. FB-2 cells only partially retained the differentiated thyroid phenotype. In fact, the PAX-8 gene, which codes for a transcriptional factor required for thyroid cell differentiation, was expressed, while thyroglobulin, TSH-receptor and thyroperoxidase genes were not. Moreover, FB-2 cells produced high levels of interleukin (IL)-6 and IL-8.
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PMID:Establishment of a non-tumorigenic papillary thyroid cell line (FB-2) carrying the RET/PTC1 rearrangement. 1180 85

All authors integrating the known facts into a model of thyroid carcinogenesis concur that two main histotypes of thyroid cancer exhibit different routes of molecular development. RET rearrangements are an initiating event in papillary carcinoma, and simultaneously the most characteristic mutation for this type of cancer. They are followed by further, not well recognized, mutations. RAS mutations are regarded as a crucial event in the development of follicular tumors already at the adenoma step, while in papillary cancer they belong to the spectrum of secondary mutations, enabling tumor progression. Aberrant DNA methylation, causing loss of P16 tumor supressor gene, may be a common event in both types of cancer. Aneuploidy is seen much more frequently in follicular than in papillary cancer, which also exhibits a low rate for loss of heterozygosity and microsatellite instability. Mutations of the P53 tumor supressor gene are a common feature of undifferentiated thyroid cancers and could be responsible for their aggressive phenotype. RET rearrangements have been proposed as identifying fingerprints for irradiation induced thyroid cancer in children. Our own data speak against this hypothesis. We noted a high frequency of RET/PTC3 mutations in a group of Polish children with papillary thyroid carcinoma, regarded as sporadic cancer.
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PMID:Molecular changes in thyroid neoplasia. 1182 Jun 15

Oncogenic activation of the RET receptor tyrosine kinase is common in different human cancers. We found that the pyrazolo-pyrimidine PP1 inhibited RET-derived oncoproteins with a half maximal inhibitor concentration of 80 nM. Furthermore, RET/PTC3-transformed cells treated with 5 microM of PP1 lost proliferative autonomy and showed morphological reversion. PP1 prevented the growth of two human papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1 rearrangements and blocked anchorage-independent growth and tumorigenicity in nude mice of NIH3T3 fibroblasts expressing the RET/PTC3 oncogene. These findings suggest targeting RET oncogenes with PP1 or related compounds as a novel treatment strategy for RET-associated neoplasms.
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PMID:The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. 1186 85

TRs are transcription factors that regulate cell proliferation, differentiation, and apoptosis. They are cellular homologs of the transcriptionally inactive viral oncogene v-erbA. We tested the hypothesis that the functions of TRs could be impaired in cancer tissues as a result of aberrant expression and/or somatic mutations. As a model system, we selected human thyroid papillary cancer, in which the most common abnormalities, RET/papillary thyroid cancer rearrangements (fusion of RET kinase domain to the activating domains of other genes), were found in 40--45% of cases. We found that the mean expression levels of TR beta mRNA and TR alpha mRNA were significantly lower, whereas the protein levels of TR beta 1 and TR alpha 1 were higher in cancer tissues than in healthy thyroid. Sequencing of TR beta 1 and TR alpha 1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such TR beta 1 or TR alpha 1 mutations, respectively. The majority of the mutated TRs lost their trans-activation function and exhibited dominant negative activity. These findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma.
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PMID:Functionally impaired TR mutants are present in thyroid papillary cancer. 1188 75

Since the discovery of the thyroid C-cell, considerable progress has been made regarding its origin, function, and pathology. In this article an attempt is made to summarize and update our knowledge about physiologic or reactive C-cell hyperplasia, neoplastic C-cell hyperplasia (medullary carcinoma in situ), and medullary microcarcinoma. Seldom recognized preoperatively, physiologic C-cell hyperplasia is associated with inflammatory, metabolic, and neoplastic thyroid disorders as well as with hypercalcemia. However, the pathogenesis is still unclear. Although physiologic C-cell hyperplasia may progress to medullary carcinoma, the full malignant potential is unknown. Problems related to the definition of physiologic C-cell hyperplasia are discussed. Immunohistochemistry and quantitative analysis are required for the diagnosis. By contrast, C-cell hyperplasia associated with MEN II syndromes or familial medullary carcinoma can be diagnosed preoperatively in asymptomatic children or adolescents by the detection of germline mutations of the RET protooncogene. Morphologic and genetic abnormalities support the idea that C-cells in the familial form of C-cell hyperplasia are neoplastic and can be recognized with conventional stains. Therefore, the number of C-cells is irrelevant for the diagnosis. Medullary microcarcinoma is a neoplasm that measures < 1 cm. The sporadic variant is usually an incidental microscopic finding, whereas the familial form can be diagnosed by genetic testing. Its morphologic features and biologic behavior differ from those of larger medullary carcinomas. The frequency of medullary microcarcinoma will probably increase with the use of genetic testing.
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PMID:C-cell hyperplasia and medullary thyroid microcarcinoma. 1191 70

Noninvasive thyroid nodules that exhibit borderline morphological signs of papillary cancer are difficult to diagnose and we do not know if they represent papillary carcinoma precursor lesions. Forty-six such nodules were analyzed for RET activation by immunohistochemistry and, in selected cases, by reverse transcriptase-polymerase chain reaction performed on RNA extracted after laser capture microdissection (LCM) of the tumor foci with and without papillary carcinoma features and positive RET immunoreactivity. RET immunoreactivity was identified, at least focally, in 30 of 46 (65.2%) of the nodules where it closely paralleled the morphological changes. Enough RNA was obtained after LCM in seven samples. RET/PTC1 or RET/PTC3 were detected in microscopic foci with papillary carcinoma features in most of the thyroid nodules (five of seven cases). No RET/PTC1 or RET/PTC3 rearrangements were detected in areas of the same tumors that lacked the cytological alterations. Analysis of clonality in the same nodules selected for LCM demonstrated that two were monoclonal and six were polyclonal. We conclude that RET activation closely parallels the morphological changes, that it is restricted to those areas of the tumor with the cytological alterations and that it is detectable in both mono- and polyclonal tumors. Although the finding of microscopic foci indicative of papillary carcinoma in a hyperplastic or adenomatous nodule does not justify the interpretation of the entire lesion as papillary carcinoma, it is possible that such foci may precede the development of invasive papillary cancer.
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PMID:Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma: a search for the early precursors of papillary cancer. 1205 97

The genes implicated in thyroid carcinoma can be categorized as oncogenes or tumor-suppressor genes. The RET oncogene has well-established roles in the development of both medullary and papillary thyroid carcinoma (PTC). Genetic testing for the germline RET mutation is commonly performed, and prophylactic thyroidectomy is carried out at an early stage. The demonstration of a RET rearrangement in a PTC patient may be prognostic factor. TSH-R and Gs alpha are associated with the development of toxic thyroid adenoma (AFTN). The ras oncogene is implicated in the early stages of development of several tumor types. In conclusion, germline screening for RET mutations is now commonly undertaken in patients with medullary thyroid carcinoma.
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PMID:[Thyroid carcinoma: genetics, diagnosis, clinical features, and surgical treatment]. 1209 2


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