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 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

Small cell carcinoma of the breast is an uncommon neoplasm that has been reported rarely in the literature. The aim of this study was to characterize better the pathologic and immunohistochemical features of this neoplasm. Nine examples of mammary small cell carcinoma were retrieved from the authors' consultation files and reviewed. The patients ranged in age from 43 to 70 years. Two patients had a previous history of cutaneous malignant melanoma and one had prior lobular carcinoma in situ and atypical duct hyperplasia in the same breast as the small cell carcinoma. Eight patients presented with a mass in the breast; one patient had an axillary tumor. Tumor size ranged from 1.3 to 5.0 cm (mean, 2.6 cm). Histologically, the nine tumors had characteristics of small cell carcinoma with high mitotic activity and necrosis. A dimorphic histologic appearance was observed in four tumors. In one instance, this consisted of small cell carcinoma merging with invasive lobular carcinoma. In three cases, small cell carcinoma was present together with invasive, poorly differentiated duct carcinoma; invasive carcinoma with "lobular and gland-forming elements"; and focal squamous differentiation, respectively. Lymphatic tumor emboli were identified in four instances. An in situ component was seen in seven tumors; five were of the small cell type in ducts and two were of the ductal type with high nuclear grade. Immunohistochemical analysis showed consistent staining for cytokeratin markers but variable staining with neuroendocrine markers. Sixty-six percent of the tumors (six of nine) were reactive for chromogranin, synaptophysin, or peptide hormones, including four positive for chromogranin and synaptophysin, one positive for synaptophysin and calcitonin, and one positive for calcitonin alone. One tumor that was reactive for chromogranin and synaptophysin also contained calcitonin immunoreactive cells, whereas gastrin-releasing peptide was present in two other tumors that were also positive for chromogranin. Leu 7 was positive in three cases that were reactive for either chromogranin or synaptophysin. Five tumors were estrogen and progesterone receptor-positive. All tumors were positive for bcl-2 and negative for HER2/neu. Patients were treated by mastectomy (n = 3) or lumpectomy (n = 6). Eight underwent an axillary dissection that revealed metastatic carcinoma in four patients. Seven patients received adjuvant chemotherapy and four patients received radiation. Two patients also received tamoxifen treatment. Metastases developed in two patients (22%) with a follow-up period of 11 and 32 months. All patients were alive at last follow up 3 to 35 months after treatment. When compared with published reports of mammary small cell carcinoma, our results show that the prognosis in these patients may not be as poor as previously suggested.
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PMID:Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. 1139 67

Germ line mutations of the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2A (MEN 2A), an inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. To study the mechanism of tissue-specific tumor development by RET with a MEN2A (cysteine 634-->arginine) mutation, we generated transgenic mice by introducing the RET-MEN2A gene fused to Moloney murine leukemia virus long terminal repeat. Expression of the transgene and its product was detected at variable levels in a variety of tissues including thyroid, heart, liver, colon, parotid gland, and brain. All of 29 mice analyzed developed thyroid C-cell hyperplasia or medullary carcinoma, accompanying high levels of serum calcitonin. In addition, development of mammary or parotid gland adenocarcinoma was observed in one-half of the transgenic mice. RET dimerization and its complex formation with Shc and Grb2 adaptor proteins were detected in tumor tissues. Unexpectedly, no tumor formation was found in other tissues despite RET-MEN2A expression where RET dimerization was undetectable. Because these tissues but not tumors expressed glial cell line-derived neurotrophic factor family receptor alpha (GFR alpha) at high levels, this suggested that GFR alpha expression may interfere in the dimerization of the RET-MEN2A mutant proteins, leading to tissue-specific tumor development in vivo.
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PMID:Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation. 1101 55

Compared to hereditary medullary thyroid carcinoma (MTC), sporadic MTC tends to be unicentric and confined to one lobe. Patients with sporadic MTC usually undergo total thyroidectomy because of a possible hereditary or bilateral process. We evaluated the usefulness of germline RET oncogene mutation analysis in surgery for apparently sporadic MTC and performed unilateral surgery on patients without detectable mutation. In 36 patients with a preoperative diagnosis of apparently sporadic MTC, we performed germline RET oncogene mutation analyses: before surgery in 8 recent patients and after surgery in 28 who had been treated before 1996. Of the latter, 5 had bilateral MTC. DNA samples were extracted from their peripheral blood, and the polymerase chain reaction products of the RET proto-oncogene were analyzed using single-strand conformation polymorphism analysis and the direct sequencing methods. Before 1996 we often performed total thyroidectomy but changed to hemithyroidectomy thereafter, except in one patient with associated Graves' ophthalmopathy. Our minimal standard practice included systematic central and ipsilateral neck dissection. The outcome was assessed in terms of gastrin- and calcium-stimulated plasma calcitonin levels. Germline RET mutations were found in six patients. Five of these patients had bilateral MTC, whereas all 30 patients without mutation had unilateral disease. Hemithyroidectomy in seven of our recent patients resulted in normalization of plasma calcitonin levels in all, although four were found to have microscopic lymph node involvement. In conclusion, hemithyroidectomy with systematic central and ipsilateral neck dissection is an appropriate procedure for patients with sporadic MTC without detectable germline RET mutations.
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PMID:Unilateral surgery supported by germline RET oncogene mutation analysis in patients with sporadic medullary thyroid carcinoma. 1103 8

The discovery of osteoprotegerin (OPG), osteoprotegerin ligand (OPGL), and RANK has elucidated the mechanism by which osteoblasts and stromal cells regulate osteoclastic differentiation and function and mediate the effects exerted by other hormones and cytokines. We have investigated the effects of these novel cytokines on the preosteoclastic cell line FLG 29.1. We show that OPGL alone and in combination with macrophage colony-stimulating factor (CSF-1) dramatically reduced replication and increased tartrate-resistant acid phosphatase activity. However, although FLG29.1 cells appear to adhere to the bone surface, they are not able to form resorption lacunae. OPG and calcitonin completely abolished the differentiation induced by OPGL. RANK was detectable in FLG 29.1 and the number of positive cells was increased by OPGL/CSF-1 treatment while reduced by calcitonin. We propose that calcitonin could interact with the OPG/OPGL, and its effects on RANK may explain in part the action of this hormone in suppressing bone resorption.
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PMID:Modulation of the effects of osteoprotegerin (OPG) ligand in a human leukemic cell line by OPG and calcitonin. 1111 97

Familial thyroid cancer can arise from parafollicular cells (familial medullary thyroid cancer) or from follicular cells (familial nonmedullary thyroid cancer). Familial medullary thyroid cancer may occur in isolation or as part of multiple endocrine neoplasia (MEN) type II syndromes. Genetic testing for a RET mutation on chromosome 10 is used to identify new family members who are gene carriers. Total thyroidectomy should be used in gene carriers without clinical disease before age 6 in medullary thyroid cancer and MEN type IIA, and as soon as the diagnosis is made in MEN type IIB after the first year of life. Those with clinical disease should have at least a bilateral central neck dissection. Modified radical neck dissection is recommended for patients when the primary tumor is 1.5 cm. A normal postoperative serum calcitonin level suggests that the operation has been curative. Physicians need to be aware of ethical and lifestyle issues related to patients with familial disease and their family members. Familial nonmedullary thyroid cancer occurs as a discrete entity or as part of other family cancer syndromes such as Gardner syndrome, Cowden disease, and other rare syndromes. Familial nonmedullary thyroid cancer almost exclusively includes patients with papillary or Hurthle cell cancers. These families appear to have more benign thyroid conditions. The gene (or genes) for familial papillary thyroid cancer is yet to be identified, whereas that for some Hurthle cells (TCO) has been mapped to chromosome 19p13.2. Familial nonmedullary thyroid cancer is somewhat more aggressive than its sporadic counterpart, but is less aggressive than medullary thyroid cancer. Total thyroidectomy and central neck dissection followed by radioactive iodine ablation and thyroid hormone suppression appear to be the most effective therapy.
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PMID:Familial thyroid cancer. 1114 85

In hereditary medullary thyroid carcinoma (MTC), few genotype-phenotype correlations have been established. RET genotypes (exons 10, 11, 13, and 14) of 63 patients with hereditary MTC (from November 1994 to October 1999) were correlated with age at diagnosis, sex, the TNM system, and basal calcitonin levels. Mutations in exons 10, 11, 13, and 14 were demonstrated in 22% (14 of 63), 54% (34 of 63), 21% (13 of 63), and 3% (2 of 63). The median ages at diagnosis differed significantly (38, 27, 52, and 62 yr; P = 0.003). When grouped by cysteine codons (exons 10 and 11 vs. exons 13 and 14), this difference became even more evident (30 vs. 56 yr; P = 0.001). Apart from age at diagnosis, no other significant associations were noted. Based hereon, three MTC risk groups were devised according to genotype: a high risk group (codons 634 and 618) with the youngest ages of 3 and 7 yr at diagnosis; an intermediate risk group (codons 790, 620, and 611) with ages of 12, 34, and 42 yr; and a low risk group (codons 768 and 804) with ages of 47 and 60 yr, respectively. Age at diagnosis was unrelated to specific nucleotide and amino acid exchange within each codon. The current data demonstrate that there is a significant genotype-phenotype correlation, allowing for a more individualized approach to the timing and extent of prophylactic surgery.
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PMID:Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. 1123 93

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy. About 75% are sporadic (sMTC) while the remaining 25% are hereditary (hMTC). The treatment of choice for both sMTC and hMTC is surgery. An adequate initial operation provides the best chance of cure. Hence, the diagnosis of MTC should be made preoperatively. In sMTC, ultrasound, ultrasound-guided fine-needle aspiration cytology and measurement of calcitonin levels (basal and after injection of calcitonin-stimulating reagents, e.g., pentagastrin) are sensitive diagnostic tools. In hMTC, identification of a germline mutation in the proto-oncogene RET is sufficient for making the diagnosis. Total thyroidectomy is recommended in all patients, sporadic and hereditary. In addition, lymphadenectomy of the cervicocentral and both cervicolateral compartments should be performed. The only indication to perform a less extensive operation may be given in young patients with hMTC. Sufficient treatment of MTC beyond local disease is still non-existent. Future research should concentrate on this issue.
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PMID:Diagnosis and therapy of sporadic and familial medullary thyroid carcinoma. 1126 Aug 60

In about 25% of cases medullary thyroid carcinoma (MTC) is hereditary. In this group is possible to detect germline point mutations of the RET proto-oncogene in about 95% of the studied cases. The purpose of the present paper is to confirm the value of the RET in the screening of the hereditary MTC. We studied 43 subjects at risk for a Multiple Endocrine Neoplasia Type 2A Syndrome. RET analysis was positive for MEN 2A in 22 subjects. Fifteen of the 22 have undergone a total thyroidectomy at our facility. Histopathological study of the surgical specimens confirmed the presence of a MTC in all the cases. According with our experience. RET analysis is a 100% sensitive and specific method of hereditary MTC screening, and we think it has obvious advantages over the calcitonin tests in technical, economic and ethic aspects.
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PMID:[Usefulness of RET proto-oncogene in the diagnosis of hereditary-type medullary carcinoma of the thyroid. Correlation with surgical findings]. 1126 81

Germline mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In the absence of biochemical and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with MEN 2A disease display the same phenotype of FMTC disease, although prognosis and clinical management in both affected and unaffected familial members are quite different. We studied a family with hereditary MTC, whose proband was referred to us because of enlarged cervical nodes and increased calcitonin serum levels 28 years after the total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently the presence of MTC metastasis was histologically confirmed. A RET genomic mutation at codon 634 (TGC-->TTC) was identified in the proband and in seven out of 19 familial members studied. Accordingly, a hereditary disease was suggested. However, the strong association of RET mutation at codon 634 with the presence of pheochromocytoma in MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during the follow-up pheochromocytoma was subsequently identified in the proband. This finding suggests that all families with a pedigree suggestive of FMTC should be regarded at risk from MEN 2A disease, at least when a critical mutation in the RET cysteine domain is detected.
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PMID:A large family with hereditary MTC: role of RET genetic analysis in differential diagnosis between MEN 2A and FMTC. 1128 Jul 16


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