Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins.
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PMID:[Neural crest and multiple endocrinopathies]. 907 21

Between 1988 and 1995 we treated ten patients aged 7-18 years for familial MTC or MEN II syndrome with a total of 17 operations. Using these surgical procedures, 6/9 patients remained free of tumor after 0-8 years (mean 4.5 years). In conclusion, we recommend thyroidectomy [1] in children younger than 5 years of age and a family history of MEN IIa; [2] in children younger than 3 years of age, presenting the characteristic phenotype of MEN IIb, both with a positive test for mutation of the RET protooncogene [4].
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PMID:[Surgical procedure in children with medullary thyroid gland carcinoma with reference to multiple endocrine neoplasia type II]. 910 31

Genetic alteration of the RET proto-oncogene is associated with multiple endocrine neoplasia type 2A and 2B (MEN 2A and MEN 2B), familial medullary thyroid carcinoma (FMTC) and Hirschprung's disease. Oncogenically activated RET has also been demonstrated in sporadic medullary thyroid tumors, which in some cases show somatic missense mutations. We have recently described a complex 9 bp deletion in RET exon 11 in a single case of sporadic MTC. In order to determine the prevalence of this mutation among sporadic MTC tumors, we have now analysed 15 cases and five normal controls by PCR-based nonradioactive single-strand conformational polymorphism analysis (PCR-SSCP) and fragment size analysis of exon 11. DNA was extracted from microdissected tumor tissue or normal cells and subjected to nested PCR prior to analysis. A markedly divergent SSCP pattern and a PCR fragment 9 bp shorter than normal were demonstrated in 14 of the 15 MTC tumors. Sequencing revealed the deletion of nine bases encompassing a key cysteine at codon 634, often altered in MEN 2A. Four lymphocyte controls and normal thyroid tissue from one patient failed to show the deletion. Several factors in the DNA sequence environment immediately surrounding the deletions, including an extended inverted repeat, several direct repeats and a so-called symmetric element suggest that the deletional events may be non-random.
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PMID:A complex nine base pair deletion in RET exon 11 common in sporadic medullary thyroid carcinoma. 916 Aug 84

Mutations in the RET proto-oncogene have recently been recognized to be responsible for the inherited multiple endocrine neoplasia type 2 syndrome. As expected, Greek patients with MEN2 and FMTC carry RET mutations similar to those of other ethnic groups. In those regions of the gene that were analyzed, mutations were detected in six out of six families with classical MEN2A, three out of five of the families with familial MTC, and one case with MEN2B. Presymptomatic screening using DNA analysis has now replaced calcitonin stimulation tests in the offspring of families where the mutation has been characterized. The use of these methods will improve the prognosis in MEN2 patients and will also reduce the psychological burden of risk for a potentially lethal disease on family members.
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PMID:Genetic screening for RET mutations in families with multiple endocrine neoplasia 2 syndromes. 923 92

Germline mutations in the RET proto-oncogene are seen in the majority of patients with the dominantly inherited cancer syndromes multiple endocrine neoplasia type 2 (MEN 2). The clinical subtypes of MEN 2 (MEN 2A, MEN 2B and familial MTC) all have medullary thyroid carcinoma, but vary in the involvement of pheochromocytoma, parathyroid adenoma/hyperplasia and developmental abnormalities. A single RET mutation, resulting in the substitution M918T, has been identified in 94% of cases of MEN 2B (which consists of MTC, pheochromocytoma and developmental abnormalities). Here we report the identification of a new germline RET mutation (A883F) in two de novo cases of MEN 2B. Identification of this new mutation will contribute to understanding the molecular basis of MEN 2B, and will assist in the clinical management of families harbouring this mutation.
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PMID:Germline mutation of RET codon 883 in two cases of de novo MEN 2B. 929 15

Germline mutations in the RET proto-oncogene have been shown to be the underlying cause of multiple endocrine neoplasia type 2 (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). Some cases of sporadic medullary thyroid carcinoma (sporadic MTC) are reported to have specific codon 918, 883 and 768 mutations of the RET gene in tumor tissues. We examined RET gene mutations in 40 Japanese cases who had previously undergone surgery for sporadic MTC. DNA extracted from formalin-fixed tumor tissues and corresponding normal thyroid tissues or peripheral blood leukocytes was analyzed for mutations of exon 10, 11, 13, 14 and 16 of the RET gene by DNA sequencing and by mutation-specific restriction enzyme analysis. Germline RET point mutations were found in six of 40 cases (15%), cysteine residues at codon 618 in two, codon 634 in three and valine residue at codon 804 in one, and were newly identified as heritable MTC. Of the remaining 34 sporadic MTC cases, four (12%) had tumor-specific RET point mutations. Two were found in exon 16; one case showed an ATG to ACG (Met to Thr) mutation at codon 918, and the other showed two point mutations, ATG to ACG (Met to Thr) at codon 918 and GCA to GTA (Ala to Val) at codon 919 with loss of the wild-type allele, suggesting that both alleles at the RET locus were altered. The other two were found in exon 13; one case showed a CCG to TCG (Pro to Ser) mutation at codon 766 and the other showed a silent mutation, GTC to GTT (Val) at codon 778 with loss of the wild-type allele. There was no association of sporadic mutations with recurrence or prognosis in patients with sporadic MTC. The low rate of somatic RET mutation at codon 918 in our sporadic MTC suggests that as yet unknown factors may be involved. Genetic alterations in both alleles may have an important role in small fraction of sporadic MTCs.
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PMID:Novel point mutations and allele loss at the RET locus in sporadic medullary thyroid carcinomas. 961 47

The RET proto-oncogene encodes a receptor tyrosine kinase expressed in neural crest derived tissues. Germline mutations in the RET proto-oncogene are responsible for three different dominantly inherited cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC). MTC can also occur sporadically. Molecular characterisation of the RET proto-oncogene has been performed by PCR-SSCP analysis, direct DNA sequencing, and restriction enzyme analysis in 49 unrelated, Spanish, MEN 2 families: 30 MEN 2A families, six FMTC families, and 13 families classified as "other". Germline missense mutations in one of six cysteine codons (609, 611, 618, and 620 in exon 10, and codons 630 and 634 in exon 11), which encode part of the extracellular cysteine rich domain of RET, have been detected in the majority of these families: 100% of MEN 2A families, 67% of FMTC families, and 54% of families classified as "other". No RET mutations in exons 10, 11, 13, 14, 15, or 16 were detected in the remaining families. The most frequent RET mutation in MEN 2A Spanish families is C634Y, occurring in 73% of cases. Haplotype analysis does not exclude the possibility of founder effects in Spanish MEN 2A families with the C634Y mutation.
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PMID:High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain. 995 Mar 71

The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.
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PMID:Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. 1002 19

Familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A syndromes are dominantly inherited diseases caused by activating germline mutations of the RET protooncogene. The majority of these patients carry a germline point mutation affecting one of five cysteine residues encoded by exon 10 (codon 609, 611, 618, or 620) or 11 (codon 634). In a few FMTC families, point mutations involving noncysteine codons in exon 13 (codons 768, 790, and 791), 14 (codon 804), or 15 (codon 891) have been reported. Hirschsprung's disease is a nonneoplastic disorder associated with RET mutations leading to a loss of function effect. Mutations are identified in 50% of the familial cases and are scattered along the gene. We now report the study of a FMTC family with four affected members and a history of fatal neonatal intestinal obstruction in the sister of the proband. Genetic analysis demonstrated the absence of an usual FMTC mutation and the presence of a germline 9-bp duplication in RET exon 8 in the heterozygous state in all patients with MTC. This new mutation creates an additional cysteine residue in the extracellular cysteine-rich domain of RET. Further studies are warranted to confirm whether this new mutation is causing MTC only or could be associated with Hirschsprung's disease.
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PMID:A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma. 1032 3

INTRODUCTION AND DISCUSSION: Molecular genetic investigations relating to thyroid cancer have started to gain clinical importance, with discovery of the tumor-specific oncogenes PTC 1-3 in papillary thyroid cancer and the syndrome-specific mutations of the RET protooncogene in MEN-2a, MEN-2b and familial MTC patients. Furthermore, the thyroid-specific sodium-iodine symporter, causing iodine accumulation in thyroid tissue, has been cloned and now offers studies to enhance iodine and radioiodine uptake in thyroid cancer, which could soon prove to be clinically applicable.
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PMID:Studies of oncogenes and tumor-suppressor genes in human thyroid carcinomas, and their clinical implications. 1036 23


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