Gene/Protein Disease Symptom Drug Enzyme Compound
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Pheochromocytomas (PCCs) are neuroendocrine tumors of chromaffin tissue that produce catecholamines. They are usually located in the adrenal medulla, although in about 10% the tumors arise from extra-adrenal chromaffin tissue. The majority of PCCs arise sporadically, but PCCs occur also in the context of hereditary cancer syndromes. Familial PCC is inherited as an autosomal dominant trait alone or as a component of the multiple endocrine neoplasia Type 2 (MEN2) syndrome (RET gene), Von Hippel-Lindau (VHL) disease (VHL gene), neurofibromatosis Type 1 (NF1 gene), or familial pheochromocytoma-paraganglioma (PCC-PGL) syndrome (SDHD/B and C genes). It has been reported that 24% of apparently sporadic PCCs patients harbor germline mutations in these PCC-causing genes. We investigated the contribution of the inherited PCC-causing genes in a partly retrospectively and partly prospectively obtained series of 213 apparently sporadic PCCs. Mutation analysis was performed for RET (56 cases), VHL (136 cases), and SDHD (126 cases) and SDHB (47 cases). No germline RET mutations, six (4.4%) germline VHL mutations, two (1.5%) germline SDHD mutations, and one germline (1.6%) SDHB mutation were found. In total we found germline mutations in about 7.5% of the investigated apparently sporadic PCCs. Although 7.5% germline mutations in a series of apparently sporadic PCCs are far less than the more than 20% reported in the literature, the figure is significant enough to consider germline mutation testing for each patient with PCC.
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PMID:Genetic analyses of apparently sporadic pheochromocytomas: the Rotterdam experience. 1710 80

Pheochromocytomas and paragangliomas are neural-crest-derived tumors that arise from mutations in RET, VHL, NF1, and in the genes-encoding succinate dehydrogenase (SDH) subunits B (SDHB), C (SDHC), and D (SDHD). Despite their genetic diversity, these tumors cannot be clearly distinguished on the basis of their primary mutation. We recently identified two major transcriptional programs embedded within familial and sporadic pheochromocytomas and paragangliomas using global expression profiling. This review will summarize the major results of these studies and discuss their implications. The transcription data revealed that: (a) tumors with mutations in VHL, SDHB, and SDHD genes share a transcription signature of hypoxia, angiogenesis, and oxidoreductase imbalance; (b) SDHB protein is suppressed in tumors with mutations in SDHB and SDHD, and also in a subset of tumors with VHL mutations; and (c) HIF1alpha is involved in the SDHB downregulation observed in these tumors. These results are consistent with the existence of a close interconnection between the VHL and SDH pathways mediated predominantly by hypoxia and oxidoreductase signals. It further suggests that low SDHB levels indicative of impaired mitochondrial complex II function may be a shared element of these pheochromocytomas. SDHB may thus constitute a marker for tumors with abnormal hypoxic profile.
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PMID:Transcription association of VHL and SDH mutations link hypoxia and oxidoreductase signals in pheochromocytomas. 1710 89

Hereditary adrenal pheochromocytoma is caused by germline mutations in RET, VHL, SDHB, SDHD, and NF1. As these genes differ in function, so may their pheochromocytoma phenotypes, suggesting gene-specific patterns of age-related progression to pheochromocytoma. This possibility was explored for gene carriers with a lifetime risk of pheochromocytoma in excess of 50%. Published age-standardized penetrance rates of VHL-, SDHB-, and SDHD-associated pheochromocytoma were gauged against age-standardized penetrance rates of MEN2-associated pheochromocytoma in 219 institutional carriers of RET mutations conferring highest (codon 918), high (codons 609, 611, 618, 620, 630, and 634) and least high risk (codons 768, 790, 791, 804, and 891). The highest-risk category included SDHB, SDHD, and the highest-risk RET genotype; the high-risk category VHL missense mutations and the high-risk RET genotypes; and the least-high risk category VHL truncating mutations and least-high risk RET genotypes. Detailed information on recurrence rates and intervals was available only for the RET carriers (19-31% and means of 4.3-5.5 years; all RET risk categories combined). Ipsilateral recurrences in adrenal remnants, and contralateral recurrences in virgin adrenals were comparable in incidence (27% and 39%, P=0.69; high-risk RET category) and time to recurrence (means of 4.3 vs. 5.4 year; P>0.99; high-risk RET category), discounting a major effect of tumor spillage at primary subtotal adrenalectomy on pheochromocytoma recurrence. The risk of malignancy usually is low, except for SDHB (38%). For most hereditary pheochromocytomas, endoscopic subtotal adrenalectomy is the procedure of choice. Grouping hereditary pheochromocytoma into preliminary risk categories may improve the management of gene carriers at risk of developing pheochromocytomas.
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PMID:Risk-oriented approach to hereditary adrenal pheochromocytoma. 1710 10

Following recent advances in the genetics of phaeochromocytomas and paragangliomas, the members of the European Network for the Study of Adrenal Tumours (ENS@T) Phaeochromocytoma Working Group have decided to share their genotyping data and to propose European recommendations for phaeochromocytoma/functional paraganglioma (PH/FPGL) genetic testing. Germline DNA from 642 patients was analysed by ENS@T teams. In 166 patients (25.9%) the disease was familial and caused by germline mutations in VHL (56), SDHB (34), SDHD (31), RET (31) or NF1 (14), causing von Hippel-Lindau disease, SDHB- or SDHD-PH/FPGL syndromes, multiple endocrine neoplasia type 2 (MEN 2) and type 1 neurofibromatosis (NF1), respectively. In almost 60% of inherited cases it was possible to formulate a probable genetic diagnosis based on family history and/or typical syndromic presentation. Genetic testing revealed mutations in 12.7% of cases with an apparently sporadic presentation. Several clinical characteristics, such as young age at onset, the presence of bilateral, extra-adrenal or multiple tumours or a malignant tumour, should be seen as indications for genetic testing. The ENS@T Phaeochromocytoma Working Group recommends the genetic testing of all patients with PH and FPGL and suggests a practice algorithm for the management of their exploration.
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PMID:Phaeochromocytoma, new genes and screening strategies. 1712 18

Myeloproliferative disorders (MPDs) constitute a group of hematopoietic malignancies that feature enhanced proliferation and survival of one or more myeloid lineage cells. William Dameshek is credited for introducing the term "MPDs" in 1951 when he used it to group chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) under one clinicopathologic category. Since then, other myeloid neoplasms have been added to the MPD member list: chronic neutrophilic (CNL), eosinophilic (CEL) and myelomonocytic (CMML) leukemias; juvenile myelomonocytic leukemia (JMML); hypereosinophilic syndrome (HES); systemic mastocytosis (SM); and others. Collectively, MPDs are stem cell-derived clonal proliferative diseases whose shared and diverse phenotypic characteristics can be attributed to dysregulated signal transduction--a consequence of acquired somatic mutations. The most recognized among the latter is BCR-ABL, the disease-causing mutation in CML. Other mutations of putative pathogenetic relevance in MPDs include: JAK2V617F in PV, ET, and PMF; JAK2 exon 12 mutations in PV; MPLW515L/K in PMF and ET; KITD816V in SM; FIP1L1-PDGFRA in CEL-SM; rearrangements of PDGFRB in CEL-CMML and FGFR1 in stem cell leukemia-lymphoma syndrome; and RAS/PTPN11/NF1 mutations in JMML. This increasing repertoire of mutant molecules has streamlined translational research and molecularly targeted drug development in MPDs.
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PMID:Oncogenes in myeloproliferative disorders. 1735 42

The familial forms of pheochromocytoma have recently been demonstrated to be more frequent than believed in the past. The genes currently known to be responsible for tumor formation are RET, VHL, NF1, SDHB, SDHC and SDHD. Germline mutations of these genes increase the risk of developing pheochromocytomas and/or paragangliomas which variably associate with other neoplasms and characterize diverse clinical syndromes such as MEN 2, von Hippel-Lindau (VHL), and neurofibromatosis type 1 (NF 1), or the PGL syndromes, respectively. Although the pathogenesis of pheochromocytoma/paraganglioma formation is still largely unknown, studies of the familial forms have started to uncover some pathways that favor tumor formation, such as activation of tyrosine-kinase, induction of hypoxia-inducible factors, activation of the oncogene Ras or reduced apoptosis. These studies have also demonstrated that various gene mutations can differently affect the biological characteristics of pheochromocytoma: for example, while the tumors are mostly adrenergic (epinephrine secreting) and episodically secreting in MEN 2, they are mostly noradrenergic (norepinephrine secreting) and continuously secreting in VHL. Biological variability can also be observed in the PGL syndromes where tumors develop in the head and neck and are parasympathetic in origin and non-secreting, or in the thorax and the abdomen, where they are sympathetic in origin and catecholamine secreting. Genetic testing in patients with pheochromocytomas or paragangliomas is, at present, strongly recommended and is mandatory in young patients or in cases of multiple or recurrent tumors. The clinical picture and the biological characteristics of the tumor may suggest the priority of the genes to be tested first.
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PMID:Genetics and biology of pheochromocytoma. 1742 3

Efforts to understand the pathobiology of pheochromocytomas and extra-adrenal paragangliomas have been spurred by genetic and gene expression profiling studies showing genotype-phenotype correlations in familial pheochromocytoma/paraganglioma syndromes and in some sporadic tumors. The current challenge is to relate catalogs of genetic and phenotypic markers to cell biology. Hypothetical bases for genotype-phenotype correlations include: cell of origin, pathway dependence, and functional and anatomic context. A further consideration is phenotype plasticity. Cross talk between signaling pathways provides a general framework for understanding how mutations of apparently unrelated genes might lead to the same type of tumor, and also suggests that targeted therapies might be directed either at a specific mutated gene or a downstream signal transducer. However, precise mechanisms of tumorigenesis remain unknown. An intriguing hypothesis proposes that mutations of RET, NF1, VHL, or SDH predispose to hereditary pheochromocytoma/ paraganglioma by causing defective apoptotic culling of cells that would normally be destroyed during embryogenesis. An argument favoring survival rather than mitogenesis as a common denominator is that the same mutations are rare in sporadic pheochromocytomas/paragangliomas, suggesting they only need to act during a limited developmental window. An implication is that tumor precursors could be identified and eradicated in individuals who carry the mutations.
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PMID:Molecular and cellular biology of pheochromocytomas and extra-adrenal paragangliomas. 1752 80

Multiple endocrine neoplasia type 2A (MEN2A) is a syndrome of familial neoplasias characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and hyperplasia of the parathyroid glands. RET protooncogene mutations are responsible for MEN 2A. Mutations in exons 10 or 11 have been identified in more than 96% of patients with MEN 2A. We herein report for the first time a patient with MEN 2A harboring a mutation (Gly(533)Cys) in exon 8. A 66-year old male patient was referred to our department for bilateral adrenal nodules. The patient's family history was remarkable in that his mother had pheochromocytoma. Biochemical evaluation and findings of the magnetic resonance imaging of the adrenals were compatible with the diagnosis of bilateral pheochromocytomas. The patient underwent laparoscopic bilateral adrenalectomy and histological examination confirmed the preoperative diagnosis of pheochromocytoma. Absence of phenotypic characteristics of VHL or NF1 and elevated calcitonin levels both basal and post pentagastrin stimulation, raised the possibility of MEN 2A syndrome. Total thyroidectomy was performed and histological examination showed the presence of MTC. Direct sequencing of exon 8 from the patient's genomic DNA revealed the mutation c.1,597G-->T (Gly533Cys). Although this missense point mutation has been associated with familial MTC (FMTC), to the best of our knowledge mutations in exon 8 have not previously been identified in patients with MEN 2A. In conclusion, in patients with clinical suspicion of MEN 2A syndrome, analysis of RET exon 8 should be considered when the routine evaluation of MEN 2A-associated mutations is negative. Furthermore, patients with FMTC and exon 8 mutations should also be screened for pheochromocytoma.
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PMID:A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A. 1770 47

von Hippel-Lindau disease, which is characterized by an increased risk of hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas, is caused by inactivating mutations of the VHL tumor suppressor gene. The VHL gene product, pVHL, has multiple functions, but the best documented, and the one most clearly linked to tumor development, relates to its role as the substrate recognition module of a ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) for destruction. pVHL function is often compromised in sporadic kidney cancers, and inhibitors of the HIF-responsive growth factor (vascular endothelial growth factor) are active against this disease. pVHL, by inhibiting atypical protein kinase C and hence JunB, also affects neuronal survival, as do the products of the other genes linked to familial pheochromocytoma or paraganglioma (NF1, RET, SDHB, SDHC, and SDHD). It is hypothesized that tumor-associated alleles of these genes allow primitive sympathoadrenal precursors to escape developmental culling, and that such cells are at increased risk of forming tumors.
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PMID:Von Hippel-Lindau disease. 1803 96

1. Recent clinical and fundamental research studies have revolutionized our understanding of the genetics of phaeochromocytoma (PH) and functional paraganglioma (FPGL). It was widely thought that only 10% of PH patients had familial disease and that the malignant phenotype of PH could not be diagnosed before occurrence of the first metastasis. 2. Human genetic studies have now shown that 25-30% of patients have hereditary PH due to a germline mutation in the SDHB, SDHD, VHL, RET or NF1 gene and that the identification of a germline SDHB mutation is associated with a high risk of malignancy and a poor prognosis in PH/PGL patients. 3. Fundamental research studies have shown that SDH genes are tumour suppressor genes and that succinate dehydrogenase inactivation induces abnormal stimulation of the hypoxia-angiogenesis pathway. 4. Finally various fundamental research studies, conducted through the Cortico and Medullo-surrenale: les Tumeurs Endocrines (COMETE) network in France and by other groups worldwide, have produced new recommendations for genetic counselling and testing and for the management of PH patients. They have also improved our understanding of the molecular mechanisms involved in PH tumorigenesis.
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PMID:Recent advances in the genetics of phaeochromocytoma and functional paraganglioma. 1830 24


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