Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Medullary thyroid carcinoma (MTC) occurs as a component of three well-described autosomal dominant familial cancer syndromes. Multiple endocrine neoplasia type 2A (MEN 2A) is characterized by MTC, pheochromocytomas, and parathyroid hyperplasia. Patients with the rarer multiple endocrine neoplasia type 2B (MEN 2B) syndrome develop MTC and pheochromocytomas, as well as mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a characteristic "marfanoid" habitus. Finally, MTC is transmitted in an autosomal dominant pattern in some families without associated pheochromocytomas or parathyroid hyperplasia (familial medullary thyroid carcinoma, MTC1(2). Sixty-one members of two well-characterized kindreds segregating MTC1 and 34 [corrected] members of six families segregating MEN2B were genotyped using a panel of RFLP probes from the pericentromeric region of chromosome 10 near a locus for MEN 2A. Statistically significant linkage was observed between the chromosome 10 centromere-specific marker D10Z1 and MTC1 (maximum pairwise lod score 5.88 with 0% recombination) and D10Z1 and MEN2B (maximum pairwise lod score 3.58 with 0% recombination). A maximum multipoint lod score of 4.08 was obtained for MEN2B at the position of D10Z1. In addition, 92 members of a previously unreported large MEN2A kindred were genotyped, and linkage to the pericentromeric region of chromosome 10 is reported (maximum pairwise lod score of 11.33 with 0% recombination between MEN2A and RBP3). These results demonstrate that both a locus for familial MTC and a locus for MEN 2B map to the pericentromeric region of chromosome 10, in the same region as a locus for MEN 2A. The finding that each of these three clinically distinct familial cancer syndromes maps to the same chromosomal region suggests that all are allelic mutations at the same locus or represent a cluster of genes involved in the regulation of neuroendocrine tissue development.
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PMID:Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A. 167 89

The genetic loci RET, D10S94, and D10S102 from human chromosome 10q11.2 are very closely linked to a locus responsible for the multiple endocrine neoplasia type 2 (MEN2A and MEN2B) and medullary thyroid carcinoma (MTC1) familial cancer syndromes. We have constructed a 1.5-megabase contig consisting of six genomic yeast artificial chromosome clones which include these loci and define their physical order. A critical crossover event has been identified within the map interval; this event places the MEN2A locus centromeric to D10S102 and defines the orientation of the physical map on the chromosome. The orientation of the contig and order of the markers are centromere-RET-D10S94-D10S102-telomere. In addition, a microsatellite repeat polymorphism with a heterozygosity of 71% at the RET locus and a restriction fragment length polymorphism with a heterozygosity of 42% detected by a lambda clone from the D10S94 locus have been developed for high-resolution genetic linkage mapping and predictive diagnostic testing. These data place three important markers on a contiguous physical map, narrow the MEN2 disease locus interval, and provide a framework for further candidate gene identification efforts. Placement of these genetic loci along a clone-based map and continued expansion of the contig will also facilitate efforts to determine the relationship of physical to genetic distance near the centromeres of human chromosomes.
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PMID:A 1.5-megabase yeast artificial chromosome contig from human chromosome 10q11.2 connecting three genetic loci (RET, D10S94, and D10S102) closely linked to the MEN2A locus. 809 42

Inherited predisposition to phaeochromocytoma is seen in multiple endocrine neoplasia type 2 syndromes, von Hippel-Lindau (VHL) disease, and neuro-fibromatosis type 1. In addition familial phaeochromocytoma alone has been reported. To investigate the genetic basis for familial phaeochromocytoma alone, we screened three affected kindreds for mutations in the RET proto-oncogene and the VHL tumour suppressor gene. We did not detect MEN 2 associated RET mutations in any family, but missense VHL gene mutations (V155L and R238W) were identified in two kindreds with no clinical evidence of VHL disease. Patients with familial, multiple, or early onset phaeochromocytoma should be investigated for germline VHL and RET gene mutations as the molecular diagnosis of multisystem familial cancer syndromes enables appropriate counselling and screening to be provided.
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PMID:Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. 859 33

Molecular genetics researchers have recently identified several genes (and mutations) that result in family cancers. This has prompted the development of molecular diagnostic tests to identify individuals at risk, making it possible to prevent certain types of cancer. However, detection and prevention of certain malignancies are impeded because few medical practitioners know of these tests, and because patients fear the emotional consequences of testing. To highlight some of these issues, we describe a patient who chose to be tested for the RET gene mutation. The mutation was identified, additional family members were tested, and several were found to be at risk. The RET gene mutation is 100% predictive for the ultimate development of medullary thyroid cancer. Testing and counseling provided this patient and her family with information not only about the thyroid cancer in their family, but also about multiple endocrine neoplasia, a syndrome resulting from mutation of this particular gene. Familial cancer clinics are being established to assist patients and physicians who face questions about familial diseases and the value of genetic testing. We include in this report information about the familial cancer clinics in Minnesota and list the services and testing opportunities available at these clinics.
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PMID:Genetic testing for familial cancer. A clinician's perspective. 863 87

The recent remarkable progress in molecular biology has revealed that various kinds of genetic alteration occur in cancers. Recently, many genes that cause hereditary cancer have been identified. For example, hMSH2 and hMLH1, which are known as DNA mismatch repair genes have been found to cause HNPCC (hereditary non-poliposis colorectal cancer). Mutation of RET oncogene has been recognized in the families of MEN (multiple endocrine neoplasia) type II. Mutations of the tumor suppressor genes are the most common changes in the genes of familial cancer. BRCA1 and BRCA2 are tumor suppressor genes that have recently been identified as familial breast and ovarian cancer, familial breast cancer genes. This paper reviewed the hereditary cancer families in which genetic alterations have been revealed and the recent progress in mapping and cloning of familial breast cancer candidate genes which have not been identified.
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PMID:[Familial cancer and oncogenic factors]. 867 87

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 parafollicular 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-phenotype 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.
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PMID:RET proto-oncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. 916 49

The molecular genetics of endocrine tumours is an area of great interest, due to the heterogeneity of endocrine tumour types, the association of hormone over-production in some cases, and the wide variation in tumour behaviour. Genes implicated fall into functional categories such as oncogenes, in which mutations tend to cause activation, and tumour suppressor genes, in which mutations lead to loss of function. Oncogenes include the receptor tyrosine kinases such as RET, signal transduction proteins and other molecules such as cell cycle regulators and nuclear proteins. Tumour suppressor genes include cell cycle regulators such as p53 and other molecules such as the MEN 1 gene. Loss of heterozygosity studies help in the initial localisation of the latter. Endocrine tumours, as with other tumours, develop as a result of a combination of genetic events, and in the paediatric age group they often occur in the setting of familial cancer syndromes. In this review we analyse the main genetic lesions which have been described in endocrine tumours. There has been an explosion of knowledge in the last 5 years including the identification of the causative genes for MEN 2 and most recently for MEN 1. Characterisation of such genes also aids in the study of somatic mutations in sporadic versions of the same tumour types as occur in the familial syndromes. Identification of a genetic predisposition to a certain tumour has management implications that are still to be clarified in most cases, although in the case of MEN 2 the guidelines for prophylactic thyroidectomy are generally well accepted.
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PMID:The molecular genetics of endocrine tumours. 964 36

Specific germline mutations in the RET proto-oncogene predispose to the familial cancer syndromes: multiple endocrine neoplasia (MEN) types 2A and 2B, and familial medullary thyroid carcinoma. Expression of the RET receptor tyrosine kinase is tightly restricted to tumours of neural crest origin, such as neuroblastoma, and neuroblastoma has been observed in RET transgenic mice. Neuroblastoma tumour cell lines transfected with the MEN2A RET gene exhibit spontaneous neuritic differentiation, whereas MEN2B-type RET transfectants demonstrate altered cell adhesion and enhanced metastatic potential. In this study, the authors examined genomic DNA from 26 primary neuroblastoma tumours for MEN2A and MEN2B RET mutations, using restriction enzyme digestion of polymerase chain reaction products as an alternative to direct sequencing. Examination of RET exons 10 (codons 611, 618, 620), 11 (codons 632, 633, 634) and 16 (codon 918) in all 26 tumours revealed no RET mutations. Taken together these data suggest that abnormalities of the RET signalling pathway, rather than oncogenic, MEN2-type RET activation by mutation, may play a role in neuroblastoma tumorigenesis.
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PMID:Absence of MEN2A- or 2B-type RET mutations in primary neuroblastoma tumour tissue. 972 1

Germline mutations in the tyrosine-kinase domain of the MET proto-oncogene were found in patients suffering from the hereditary predisposition to develop multiple papillary renal-cell carcinomas (hereditary PRCC, HPRCC). PRCCs are often multiple and bilateral even in patients without a family history. We analyzed the germline of patients carrying multiple or single papillary tumors with and without family history. One patient had a familial cancer and carried a novel (V1110I) germline MET mutation, located in MET gene exon 16. This mis-sense mutation was found in affected members of this patient's family. Interestingly, the V1110I mutation is located in the ATP-binding site of the MET kinase and is homologous to the V157I mutation that triggers the sarcomagenic potential of the v-erbB oncogene. The V1110I mutated MET receptor is an active kinase and transforms NIH-3T3 fibroblasts in the in vitro assays. Patients without familiality did not show germline mutations in the MET kinase domain, showing that multiple and bilateral papillary kidney tumors develop in the absence of these mutations. In conclusion, we describe a new mutation in the MET oncogene kinase domain, associated to HPRCC, affecting an amino-acid residue critical for kinase activation in different oncogenes.
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PMID:Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family. 1041 59

Multiple endocrine neoplasia type 2B (MEN 2B) is a familial cancer syndrome, in which the cardinal feature is medullary thyroid carcinoma (MTC), a malignant tumor arising from the calcitonin producing thyroid C-cells. MEN 2B is associated with a germline point mutation in the RET proto-oncogene, leading to a Met-->Thr substitution at codon 918 in the kinase domain, which alters the substrate specificity of the protein. We used the human calcitonin gene (CALC-I) promoter to generate transgenic mice expressing either the human RET oncogene with the MEN2B-specific 918 Met-->Thr mutation (CALC-MEN2B-RET) or the human non-mutated RET proto-oncogene (CALC-WT-RET) in the C-cells. At 20 - 22 months of age three out of eight CALC-MEN2B-RET transgenic founders presented with macroscopic bilateral MTC. In two founders nodular C-cell hyperplasia (CCH) was observed. Thyroid abnormalities were never observed in CALC-WT-RET transgenic mice or control non-transgenic mice analysed at this age. In some mice from established CALC-MEN2B-RET transgenic lines nodular CCH was observed from 8 months on whereas MTC was detected in 13% of mice from one CALC-MEN2B-RET line, from the age of 11 months on. These results show for the first time that the MEN2B mutation in the RET oncogene predisposes mice for MTC.
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PMID:Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice. 1087 66


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