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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
...
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.
...
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.
...
PMID:Medullary thyroid carcinoma. Genetic screening and prophylactic thyroidectomies. 1517 67

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.
...
PMID:RET polymorphisms in codons 769 and 836 are not associated with predisposition to medullary thyroid carcinoma. 1535 Jun 25

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.
...
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

Recent studies have focused on the occurrence of concomitant medullary-papillary thyroid carcinomas (MTC-PTC). The aims of this report were to compare the frequency of occult PTC in a population with MTC versus a control population that had undergone thyroidectomies and to check whether differences could be related to particular phenotype or genotype. To achieve these goals, we determined the frequency of occult PTC among patients operated for MTC (n = 82) or undergoing total thyroidectomy mainly for goiter and/or nodules (n = 7313) between 1994-2001. We then examined the clinical, histologic, and genetic characteristics (using a bio-chemical family inquiry and screening for RET germline mutations) of patients with associated PTC-MTC. Results show a significantly higher frequency of occult PTC in MTC (14.7%) than in total thyroidectomy (6.8%; p < 0.01). Seventeen cases of MTC or bilateral C-cell hyperplasia (CCH) and separate occult PTC were identified from 16 different families. Although common RET mutations providing evidence of familial forms of MTC were identified in only 3 of 16 families, clinical and histologic features usually seen in inherited forms of MTC such as young age of occurrence, bilateral CCH or associated case in family were found in 11 of the remaining 14 patients. In conclusion, results suggest that the association of MTC-PTC is not only a coincidence. Surprisingly, 11 of 17 MTC-PTC patients exhibited clinical, histologic, and/or family features usually encountered in familial forms despite the fact that no RET defect were present. This suggests the possible involvement of another gene or uncommon abnormality of RET gene.
...
PMID:Thyroid carcinomas involving follicular and parafollicular C cells: seventeen cases with characterization of RET oncogenic activation. 1558 81

Medullary carcinoma of the thyroid (MTC) may be sporadic or may occur on a hereditary basis. Hereditary MTC can occur either alone -- familial MTC (FMTC) -- or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or other forms. Germ-line mutations in RET cause MEN 2. Genetic testing, now available, forms the basis for MTC screening procedures. In the past few years, several genotype-phenotype correlations have focused on the relationship between specific mutations and different MEN 2 syndrome variants. Differences in dimerization induction intensities are a reasonable explanation for the phenotypes resulting from mutations of the different cysteines. Here we described the molecular mechanisms, diagnose and treatment as well as our experience on the management of this rare form of thyroid cancer.
...
PMID:[Medullary thyroid carcinoma: clinical and oncological features and treatment]. 1561 26

Medullary carcinoma of the thyroid (MTC) occurs sporadically, or in familial forms in familial medullary thyroid carcinoma and multiple endocrine neoplasia types 2A and 2B. In the familial forms it is associated with well-characterized, germline mutations in the RET protooncogene. The mutation sites differ in MEN2A and MEN2B, and MTC develops at an earlier age and is more aggressive in MEN2B. Screening of relatives of affected individuals for such mutations can identify those at risk of developing MTC and total thyroidectomy can be carried out in the first decade of life before the development of clinical disease. Analysis of such removed thyroid glands shows abnormalities of the parafollicular C-cells in almost all cases. The abnormalities range from C-cell hyperplasia, either diffuse or nodular, to microcarcinoma and occasionally frank MTC. The abnormalities are bilateral and affect the upper two thirds of the thyroid lobes. Microcarcinomas may be visible with the naked eye, but often they are identified only on microscopy. Histopathological examination of the entire gland is essential.
...
PMID:The pathology of preclinical medullary thyroid carcinoma. 1564 May 48

The RET gene is frequently mutated in papillary thyroid carcinoma and in medullary thyroid carcinoma. We have identified three different anti-RET drugs: two pyrazolo-pyrimidines, PP1 and PP2 and an anilinoquinazoline, ZD6474 (AstraZeneca). These compounds are able to inhibit RET kinase activity in vitro (IC50 dose 100 nM) and in vivo and they can prevent RET mediated transformation. Finally, mutation of RET V804 to methionine or leucine, found in MTC patients, induces resistance to the three drugs.
...
PMID:Identification of RET kinase inhibitors as potential new treatment for sporadic and inherited thyroid cancer. 1569 60

Thyroid tumors are rare in childhood and adolescence. A retrospective analysis was done of fifteen patients (8 female) with thyroid carcinoma attended in the Pediatric Endocrinology Unit of the HC-UFPR, from February 1988 to March 2003. The most frequent initial complaint was an anterior cervical nodule. Ten patients were papillary carcinoma (PTC) bearers, four had medullary carcinoma (MTC; three of them with MEN-2B) and one had follicular carcinoma. Two patients with MEN-2B have de novo proto-oncogene RET mutation (Met918Thr). Fine needle aspiration (FNA) was performed in ten patients and was malignancy positive in only five of them. All patients underwent total thyroidectomy. Adjuvant radioiodine (131I) therapy was made in ten patients. Two patients died from unrelated diseases. Nine patients presented no clinical or laboratorial evidence of disease; one (PTC) developed recurrence 5 years after initial treatment and three (1 PTC, 2 MTC) have disease evidence yet. Our prognosis and clinical manifestations data are according to the literature. However, MTC prevalence (27%), sex distribution and FNA results differ from the majority of published casuistics, that can be attributed to the number of cases reported here.
...
PMID:[Thyroid cancer in childhood and adolescence--report of 15 cases]. 1576 50


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---