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)

Clinical and genetic understanding of chromaffin tumors has been greatly enhanced in the last few years. Although some pheochromocytoma genes may still be unknown, the role of RET, VHL, SDHB, SDHD and NF1 genes is unequivocal and phenotypes are also being better characterized. The loss of function of VHL and NF1 genes can lead to a variety of tumors including phechromocytoma and their mechanism of action is under intensive investigation. Many different mutations are responsible for VHL gene inactivation but only missense mutations have been described so far in families with pheochromocytoma. Because of its large size extensive mutation analysis of the NF1 gene has seldom been performed, and mutations have only been identified in about 15% of patients. Several point mutations have been found in exon 31. Differences in pheochromocytoma phenotype in VHL or NF1 are not very pronounced, but it may be of some interest to consider the two groups separately. In VHL, pheochromocytoma has an earlier onset than in sporadic forms, it is often multiple, and malignancy is less frequent. The mean age of diagnosis is 28 years, the youngest patient being 5 years old. In NF1 patients pheochromocytoma phenotype is similar to sporadic forms. The mean age of pheochromocytoma onset is 42 years; 84% of patients have solitary adrenal tumors, 9.6% have bilateral adrenal disease and 6.1% have ectopic pheochromocytomas; malignant pheochromocytomas were identified in 11.5% of the cases. The group of pheochromocytoma susceptibility genes includes, along with the tumor suppressor genes VHL and NF1, the proto-oncogene RET and the genes encoding succinate dehydrogenase subunit D and succinate dehydrogenase subunit B. Whether there is a common pathway among these different genes is still a matter of debate.
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PMID:Pheochromocytoma in von Hippel-Lindau disease and neurofibromatosis type 1. 1588 5

Pheochromocytoma are tumors derived from chromaffin cells that secrete catecholamines. These catecholamines may lead to increased blood pressure and even death. Historically, pheochromocytoma have been described as 10 tumor, i.e. about 10 were believed to be malignant, 10 were found to be extra-adrenal, and 10 were meant to be bilateral. Also, about 10 were considered to be hereditary. In these instances, they were most often part of either the multiple endocrine neoplasia type 2 (MEN 2) syndrome or the von Hippel-Lindau (VHL) disease. The genes (RET and VHL) involved have been known for several years and their function is the subject of ongoing investigation. Very recently, several genes (SDHD, SDHB, and SDHC) that belong to the mitochondrial complex II have been identified to be involved in the so-called pheochromocytoma-paraganglioma syndrome. Only SDHD and SDHB have so far been implicated in the pathogenesis of pheochromocytoma.
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PMID:Pheochromocytoma-associated syndromes: genes, proteins and functions of RET, VHL and SDHx. 1588 6

Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counselling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific hereditary cancer susceptibility syndromes. In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors. The genetic predisposition to adrenocortical cancer in children has been well established in the Li-Fraumeni and Beckewith-Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF-2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syndrome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inactivating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and somatic PRKAR1A mutations in secreting adrenocortical adenomas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocytoma and paraganglioma, the demonstration that three genes encoding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary paraganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at-risk of disease by the presymptomatic genetic testing.
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PMID:New insights in the genetics of adrenocortical tumors, pheochromocytomas and paragangliomas. 1600 32

Mutations in VHL, RET, NF1, SDHB, SDHC, and SDHD can give rise to pheochromocytoma/paraganglioma. These different genetic lesions may all act by decreasing the activity of a 2-oxoglutarate-dependent oxygenase, SM-20/EglN3/PHD3, resulting in reduced apoptosis of neural crest cells during development.
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PMID:A common pathway for genetic events leading to pheochromocytoma. 1609 68

Pheochromocytoma and paraganglioma are rare neuroendocrine tumors that arise in the adrenal medulla and the extra-adrenal paraganglia, respectively. Inheritance of these tumors is mainly a result of mutations affecting the VHL, RET, NF1, and SDH genes. Germ-line mutations of the SDH genes have been found to account for nearly 10% of apparently sporadic cases. Nevertheless, alterations other than point mutations have not yet been well characterized. In this study, we investigated the frequency of gross SDH deletions in 24 patients who tested negative for point mutations and had at least one of the recommended features for genetic testing. For this purpose, we used a technique that is easy to implement in the lab to specifically detect gross deletions affecting SDHB, SDHC, and SDHD. We identified 3 heterozygous SDHB deletions (3/24) in 3 independent cases with paraganglioma: 1 whole SDHB deletion and 2 deletions exclusively affecting exon 1. These latter mutations match the unique gross deletion previously reported, indicating this region could be a hot spot for gross SDHB deletions. It seems likely that these alterations can account for a considerable number of both familial and apparently sporadic paraganglioma cases. Although this is the first report describing the presence of gross deletions in patients with apparently sporadic paragangliomas, the extra-adrenal location of the tumor seems to constitute a determining factor for whether to include these patients in genetic testing for gross deletions in the SDHB gene.
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PMID:Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot? 1625 55

Functioning paraganglioma and gastrointestinal stromal tumor (GIST) are uncommon tumors that occur mostly in a sporadic and isolated form, occasionally as components of multiple neoplasia syndromes, either separately or together. Separately, they occur in several inherited syndromes including multiple endocrine neoplasia 2, and the GIST, lentigines, and mast cell tumor syndrome. Together, they are variably prominent components of three syndromes: the familial paraganglioma and gastric GIST syndrome, neurofibromatosis type 1, and the Carney triad. The two former conditions are inherited as autosomal dominant traits; the latter does not appear to be inherited and affects young women predominantly. This article reports the nonfamilial occurrence of functioning paraganglioma and GIST of the jejunum in 3 women, 1 young (22 years) at initial presentation. The occurrences were unexpected because of the infrequency of the tumors. The neoplasms, respectively, did not show germline SDHA, SDHB, SDHC, and SDHD, and KIT mutations associated with familial paraganglioma and familial GIST. The paraganglioma-jejunal GIST combination may be the harbinger of a rare genetic syndrome, a variant of the Carney triad or the paraganglioma-gastric stromal sarcoma syndrome, or be coincidental.
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PMID:Functioning paraganglioma and gastrointestinal stromal tumor of the jejunum in three women: syndrome or coincidence. 1633 Sep 41

Paragangliomas (PGLs) are rare tumours arising from parasympathetic-associated paraganglia (particularly of the head and neck) or from sympathetic-associated paraganglia such as in the adrenal medulla when they are termed phaeochromocytomas and at extra-adrenal sites in the abdomen and thorax. Recent reports have found frequent germline mutations of VHL, RET, SDHB or SDHD not only in familial cases but also in apparently sporadic cases of phaeochromocytoma. These germline mutations are particularly likely to be found if multifocal disease is present or if the phaeochromocytoma or PGL occurs at a young age. We report a germline splice site mutation in SDHB in a patient presenting with an incidental, apparently sporadic, abdominal sympathetic PGL at 68 years of age.
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PMID:An apparently sporadic paraganglioma with an SDHB gene germline mutation presenting at age 68 years. 1647 67

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by mutations in the VHL tumour suppressor gene. VHL disease is characterised by marked phenotypic variability and the most common tumours are haemangioblastomas of the retina and central nervous system and clear cell renal cell carcinoma. However, endocrine tumours, most commonly phaeochromocytoma and non-secretory pancreatic islet cell cancers, demonstrate marked interfamilial variations in frequency and are significant causes of morbidity and, sometimes, mortality. Genotype-phenotype correlations have revealed that certain missense mutations are associated with a high risk of phaeochromocytoma but total loss of function mutations are associated with a low risk. Furthermore, rare mutations may predispose to a phaeochromocytoma-only phenotype. Germline VHL mutations may be detected in 5-11% of all phaeochromocytoma cases and mutation analysis of VHL and other phaeochromocytoma susceptibility genes (SDHB, SDHD and RET) should be performed in all cases of familial, multiple or early onset phaeochromocytomas, and considered in other cases. The VHL gene product has a key role in regulating the stability of hypoxia-inducible factors (HIF-1 and HIF-2) such that inactivation of VHL leads to up-regulation of HIF-1 and HIF-2 protein expression and activation of hypoxic gene response pathways. Germline SDHB and SDHD mutations also lead to increased expression of HIF target genes, but it appears that phaeochromocytoma susceptibility in VHL disease cannot be attributed to HIF activation alone. Recently, it has been suggested that an HIF-independent failure of developmental apoptosis is a common feature of all inherited phaeochromocytoma susceptibility syndromes.
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PMID:Von Hippel-Lindau disease and endocrine tumour susceptibility. 1672 71

Major advances have been made in the understanding of the genetic mechanisms underlying endocrine tumorigenesis, through the study of several syndromes of genetic predisposition and the identification of the genes involved. The syndrome of type 1 multiple endocrine neoplasia (MEN-1) is one of the best known; this autosomal dominant hereditary syndrome predisposes to the development of endocrine tumors of the pituitary, the parathyroids, the foregut and the adrenals. The responsible gene, known as MEN-1, encodes an original protein, menin, involved in several major cellular functions, such as the control of cell proliferation and differentiation. Type 2 multiple endocrine neoplasia (MEN-2) is an autosomal dominant hereditary syndrome associated with the development of medullary carcinomas of the thyroid, pheochromocytomas and hyperparathyroidism; the corresponding gene, RET, encodes a transmembrane receptor with tyrosine kinase activity. Endocrine tumors are also associated with non Hippel-Lindau disease and with phacomatoses, such as type 1 neurofibromatosis and tuberous sclerosis. Finally, isolated familial syndromes of endocrine tumors have been described: isolated familial hyperparathyroidism type II (HRPT2), associated with alterations in a gene coding for an original protein, parafibromin, or isolated familial syndromes of pheochromocytomas and paragangliomas (PRG) associated with mutations in the genes SDHB, SDHC or SDHD, which encode succinate-dehydrogenase subunits. The understanding of the genetic mechanisms underlying these syndromes of predisposition is essential for the diagnosis and management of these patients and their family; it also gives insight on the molecular mechanisms of endocrine tumorigenesis.
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PMID:[Genetics of endocrine tumours]. 1673 73

Hereditary pheochromocytomas and paragangliomas are caused by germline mutations in syndrome-associated genes. This includes multiple endocrine neoplasia Type 2 (MEN 2) caused by mutations in the RET proto-oncogene, von Hippel-Lindau (VHL) syndrome due to mutations of the VHL gene, neurofibromatosis Type I (NF1) caused by mutations of the NF1 gene, and pheochromocytoma/paraganglioma syndromes due to mutations in genes encoding the succinate dehydrogenase subunits D (SDHD) and B (SDHB). At the First International Symposium on Pheochromocytoma (ISP2005) organized by the National Institutes of Health, a panel of specialist clinicians and scientists from around the world addressed the topic of genetic testing in pheochromocytoma patients. This review summarizes the discussions and conclusions of the panel and provides a recommendation for evidence-based management of genetic testing in these patients and their families. A pragmatic algorithm is presented, taking into account patient age, tumor location (extra-adrenal, intra-adrenal, unilateral, and bilateral), biochemical presentation, and financial costs. This was based on cumulative frequencies ranging from 7.5% to 29% for germline mutations in four genes (RET, VHL, SDHB, and SDHD) in patients with apparently sporadic pheochromocytomas. This algorithm will need to be validated by further genetic analysis, multicenter studies, and long-term observations.
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PMID:Genetic testing in pheochromocytoma: increasing importance for clinical decision making. 1710 76


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