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)

Twenty five percent of the medullary thyroid carcinoma (MTC) is hereditary and 5% is familiar (FMTC), or considered as multiple endocrine neoplasia (MEN) type 2A (17%) or 2B (3%). These diseases are the result of the autosomic dominant inheritance of a mutation in the RET protooncogene, in one out of 12 different known codons. We analyzed 7 families (2 MEN 2A and 5 FMTC). Six mutations were detected in the most frequent codon, 634 (2 MEN 2A y 4 FMTC) and one family with FMTC presented a novel mutation: a transition T > C at codon 630, resulting a C630A change. Among 57 individuals studied, 25 (43.85%) presented the mutation. Seven (28%) were asymptomatic carriers, including 5 children aged 11 +/- 3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germine novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed.
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PMID:[Study of RET protooncogene in multiple endocrine neoplasm 2A and in familial medullary thyroid carcinoma. Clinical pathological findings in asymptomatic carriers]. 1267 60

Hereditary thyroid cancer in childhood occurs in the setting of Multiple Endocrine Neoplasia types 2A and 2B, and familial medullary thyroid carcinoma, FMTC. Prophylactic thyroidectomy in childhood has been recommended in patients found to have inherited mutations in the RET protooncogene, to prevent the development of medullary thyroid carcinoma. In this report are presented the clinical and genetic aspects of hereditary thyroid cancer in children, as well as surgical recommendations and medium-term outcome results.
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PMID:Management of hereditary thyroid cancer in children. 1294 81

Causative gain-of-function mutations of the RET tyrosine-kinase receptor gene have been reported in more than 95% of inherited cases of medullary thyroid carcinoma (MTC; OMIM# 155240). Most RET activating mutations are clustered in mutational "hot spots" in exons 10, 11, 13, 14, 15 and 16 and are usually detected by single-strand conformation polymorphism (SSCP) followed by direct sequencing. To improve sensitivity, time and costs of mutational screening we have developed a denaturing high performance chromatography (DHPLC) protocol, based on the detection of heteroduplex molecules by ion-pair reverse-phase liquid chromatography under partially denaturing conditions. The mutational screening of RET exons 10, 11, 13-16 was performed in a total of 111 subjects, including 45 MTC patients and 49 relatives with known RET mutations and 17 individuals, being at risk of hereditary MTC and carrying unknown RET alleles. Heteroduplex peaks with a distinct and reproducible DHPLC elution profile allowed the detection of both rare and common RET mutations. Overall, the DHPLC-based methodology showed a high level of sensitivity and accuracy, nearing 100%. Furthermore, our protocol showed the ability to identify: 1) all the mutated codons of RET located in the "hot spots" domain; 2) the different point mutations occurring in the same codon of RET gene; 3) less frequent or rare mutations; 4) polymorphisms. As such, it can be proposed as a relatively simple and highly accurate method for a rapid genetic testing for members of MTC families.
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PMID:Evaluation of a DHPLC-based assay for rapid detection of RET germline mutations in Italian patients with medullary thyroid carcinoma. 1512 4

Successful treatment of MTC depends heavily on early diagnosis and treatment. Often, this is not possible for sporadic MTC; however, genetic testing for hereditary MTC makes this possible if genetic carriers have surgery before C cells undergo malignant transformation. All patients who have MTC should be tested for RET mutations, including putative sporadic cases. The leukocytes of suspected carriers and sporadic MTC cases should be tested for MEN2-associated germ-line mutations by polymerase chain reaction amplification of the appropriate RET gene exons, including 10, 11,13, 14, 15, and 16 (see Table I). When a RET mutation is found, all first-degree relatives must be screened to determine which individuals carry the gene. If these exons are negative, the other 15 should be sequenced because a small risk of hereditary MTC remains if no germ-line mutation is found. The probability that a first-degree relative will inherit an autosomal dominant gene for MTC from an individual who has sporadic MTC in whom no germ-line mutation is found is 0.18% . Patients who have MEN2B or RET codon 883 or 918 mutation should have a total thyroidectomy within the first 6 months of life, preferably within the first month of life. Patients who have 634 mutations, which account for approximately 70% of all MTC mutations, should undergo thyroidectomy by age 5 years. The recommendations for the timing of prophylactic thyroidectomy are not consistent for the less common mutations (see Table 2). There is a balance between performing prophylactic thyroidectomy earlier than at the youngest age at with MTC has been reported to occur for a specific RET mutation (see Fig. 3 and Table 2) and the complications of thyroidectomy, including permanent hypoparathyroidism and laryngeal nerve damage. Preoperative measurement of plasma free metanephrine and neck ultrasonography always should be done if the diagnosis of MTC is known preoperatively. Initial treatment of MTC is total thyroidectomy, regardless of its genetic type or putative sporadic nature, because surgery offers the only chance for a cure. Treatment with 1311 has no place in the management of MTC. Plasma CT measurements provide an accurate estimate of tumor burden and are especially useful in identifying patients who have residual tumor. Pentagastrin- or calcium-stimulated plasma CT testing is useful in identifying CCH or early MTC in carriers of RET mutations that are associated with late onset MTC. Pheochromocytoma may occur before or after MTC and is an important cause of mortality, even in young patients. HPT is an important aspect of MEN2A and requires surgery according to current guidelines for the management of primary HPT. Early thyroidectomy and appropriate management of pheochromocytoma clearly have modified the course of this disease, but more research is necessary in kindreds who have rare MTC mutations. Moreover, new treatments for widespread MTC are necessary because current chemotherapy agents offer little benefit. New drugs that lock the action of tyrosine kinase offer some hope.
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PMID:Diagnosis and management of medullary thyroid carcinoma. 1515 57

Identifying the molecular basis for genotype-phenotype correlations in human diseases has direct implications for understanding the disease process and hence for the identification of potential therapeutic targets. To this end, we performed microarray expression analysis on benign (pheochromocytomas) and malignant (medullary thyroid carcinomas, MTCs) tumors from patients with multiple endocrine neoplasia (MEN) type 2A or 2B, related syndromes that result from distinctive mutations in the RET receptor tyrosine kinase. Comparisons of MEN 2B and MEN 2A MTCs revealed that genes involved in the process of epithelial to mesenchymal transition, many associated with the tumor growth factor beta pathway, were up-regulated in MEN 2B MTCs. This MEN 2B MTC profile may explain the early onset of malignancy in MEN 2B compared with MEN 2A patients. Furthermore, chondromodulin-1, a known regulator of cartilage and bone growth, was expressed at high levels specifically in MEN 2B MTCs. Chondromodulin-1 mRNA and protein expression was localized to the malignant C cells, and its high expression was directly associated with the presence of skeletal abnormalities in MEN 2B patients. These findings provide molecular evidence that associate the previously unexplained skeletal abnormalities and early malignancy in MEN 2B compared with MEN 2A syndrome.
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PMID:Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors. 1517 1

Medullary thyroid cancer is a rare, neuroendocrine, tumor. It arises from parafollicular or C-cells with the ability to produce and secrete different bioactive substances like calcitonin (TC) and CEA (1-5) TC is ideal tumor marker in early diagnosis, in patents' follow up and in evaluation of their treatment. TC determinations after ca/pentagastrine stimulation test give us even more accurate results and the procedure is used for biochemical family screening. MTC occurs as a sporadic tumor or in hereditary settings MEN 2A, MEN 2B and FMCT. Germ/line point mutations in RET proto/onkogene are responsible for tumor arise and inheritance of settings. Genetic screening provides information of these RET mutations in family members even before pathologic changes occur. These individuals with MEN 2A, 2B and FMCT characteristic RET mutations are almost certain to acquire MTC (95% penetrance) in their lives and are candidates for preventive total thyroidectomy (TT), with or without central neck dissection (CND). Surgery is still the treatment of choice for MTC and only C-cell hyperplasia and early stage of MTC can be cured. Prophylactic thyroid surgery eliminates the possibility of MTC but doesn't influence appearance of other diseases (PHEO, HPTH) of MEN 2 syndromes.
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PMID:Medullary thyroid carcinoma. Genetic screening and prophylactic thyroidectomies. 1517 67

The familial form of medullary thyroid carcinoma (MTC) is caused by mutations of the RET protooncogene. We registered 60 multiple endocrine neoplasia (MEN) 2A patients, 12 familial non-MEN medullary carcinoma (FMTC) patients, and three MEN2B patients with a confirmed RET germline mutation. All 60 MEN2A patients had RET mutations in a cysteine-rich domain. Seven of the FMTC patients had a mutation in cysteine-rich domain, and the other five had a mutation in codon 768, which encodes a tyrosine-kinase domain. Two of the MEN2B patients had a mutation in codon 918, and one patient had a double mutation, one in codon 804 and the other in codon 806, both of which are all encoded tyrosine-kinase domain. The genotype-phenotype correlations of our data will allow individualized recommendations for the optimal timing of prophylactic surgery.
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PMID:RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. 1527 13

The study was undertaken to verify whether the RET gene polymorphisms are associated with MTC in patients negative for germline mutations. Two hundred five patients with apparent sporadic MTC were subjected to genetic analysis of RET exons 10, 11, 13, 14, 16 and 22 RET germline mutation carriers were identified with 10.7% frequency. The frequency among 26 patients not older than 30 was 27%. In patients excluded for known mutations we analyzed two polymorphic sites: RET codon 769 and 836. As control group, 90 healthy subjects were investigated. In young patients the observed allelic frequencies were 32% for variant L769/CTG and 5% for variant S836/AGT. Although these values were higher than in older MTC patients (22 and 3%, respectively), as well as in the control group (27 and 2%) the difference was insignificant. We conclude that in Polish patients polymorphisms at RET codons 769 and 836 are not associated with medullary thyroid carcinoma.
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PMID:RET polymorphisms in codons 769 and 836 are not associated with predisposition to medullary thyroid carcinoma. 1535 Jun 25

In hereditary medullary thyroid carcinoma (MTC), recommendations regarding timing and extent of surgery are mainly based on the data of patients with the codon 634 RET mutation, which is the most often affected codon. Little is known about whether these recommendations may also be applied to patients with less common RET mutations. We ascertained the data from 140 patients with FMTC/MEN2A-related RET mutation not affecting codon 634 who have been treated at three specialized centers. The several RET mutations found affected codons 611 (n = 17), 618 (n = 22), 620 (n = 17), 768 (n = 9), 790 (n = 24), 791 (n = 21), 804 (n = 23), and 891 (n = 7). For each codon, the age of the youngest patient with MTC only (41, 7, 18, 29, 13, 47, 20, and 15 years, respectively), MTC with lymph node metastases (46, 24, 21, 34, 46, 47, 50, and 76 years, respectively), and MTC with distant metastases (52, 69, 43, 68, 57, - , - , and 75 years, respectively) was determined. All patients with lymph node metastases had elevated basal calcitonin levels. Based on these data, a more individual recommendation regarding timing and extent of surgery can be given. Because neither gender nor the type of nucleotide substitution for a specific codon appeared to have a significant influence on the age of onset, this recommendation should be based on the affected codon, the age of the patient, and the calcitonin level. Recurrent laryngeal nerve palsy (n = 6) and hypoparathyroidism (n = 3) were rather rare and were found only in patients older than 30 and 43 years, respectively, giving evidence that surgery in young patients can be performed safely.
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PMID:Timing and extent of surgery in patients with familial medullary thyroid carcinoma/multiple endocrine neoplasia 2A-related RET mutations not affecting codon 634. 1551 81

Sequence alterations in the RET proto-oncogene are becoming increasingly important to clinical assessment of the malignant disease of the thyroid. A spectrum of mutations is necessary to establish comprehensive phenotype to genotype relationship relevant to diagnosis and therapy of thyroid malignancies. We aimed to append to the increasing database of these oncogenic lesions and, therefore, analyzed DNA from tumor tissue and constitutive DNA from a patient with thyroid carcinoma. Mutational screening and sequence characterization of the RET proto-oncogene was performed to include part of the intronic sequences. We report a germline sequence variant in DNA from the patient diagnosed with microfollicular thyroid carcinoma. The carcinoma presented not as fully developed medullar carcinoma (MTC) but as microfollicular carcinoma with tendency to evolve into MTC. We characterized the sequence variant located in the intron 10 of the RET oncogene as an A to G substitution denoted IVS10 + 4G. The described sequence alteration generates a chi-like sequence surrounded by several chi-like sequences with recombinational potential. Such alteration may be involved in the pathogenesis of the microfollicular carcinoma via genome destabilization through homologous recombination in the process of tumor progression. This result further substantiates the importance of the database correlating specific sequence variations in the RET gene with distinct disease phenotypes.
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PMID:Sequence variant in the intron 10 of the RET oncogene in a patient with microfollicular thyroid carcinoma with medullar differentiation: implications for newly generated chi-like sequence. 1557 15


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