Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroblastoma is an embryonal tumour of the peripheral sympathetic nervous system (SNS). One of the master regulator genes for peripheral SNS differentiation, the homeobox transcription factor PHOX2B, is mutated in familiar and sporadic neuroblastomas. Here we report that inducible expression of PHOX2B in the neuroblastoma cell line SJNB-8 down-regulates MSX1, a homeobox gene important for embryonic neural crest development. Inducible expression of MSX1 in SJNB-8 caused inhibition of both cell proliferation and colony formation in soft agar. Affymetrix micro-array and Northern blot analysis demonstrated that MSX1 strongly up-regulated the Delta-Notch pathway genes DLK1, NOTCH3, and HEY1. In addition, the proneural gene NEUROD1 was down-regulated. Western blot analysis showed that MSX1 induction caused cleavage of the NOTCH3 protein to its activated form, further confirming activation of the Delta-Notch pathway. These experiments describe for the first time regulation of the Delta-Notch pathway by MSX1, and connect these genes to the PHOX2B oncogene, indicative of a role in neuroblastoma biology. Affymetrix micro-array analysis of a neuroblastic tumour series consisting of neuroblastomas and the more benign ganglioneuromas showed that MSX1, NOTCH3 and HEY1 are more highly expressed in ganglioneuromas. This suggests a block in differentiation of these tumours at distinct developmental stages or lineages.
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PMID:The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma. 1820 99

Neuroblastomas are biologically and clinically heterogeneous tumours that most often occur sporadically in children at median age of 2 years. The PHOX2B gene is implicated in the development of the autonomic nervous system and has been found to be infrequently mutated in sporadic neuroblastoma tumours and in some patients with hereditary neuroblastoma. We have screened a selected series of 36 paediatric tumours with presumed genetic predisposition, 34 of them neuroblastomas, for mutations in PHOX2B. A constitutional heterozygous missense mutation was found in a boy who developed bilateral adrenal tumours and stage 4 disease during infancy. The second allele of the PHOX2B locus was lost in the tumour DNA. Histopathological evaluation of the tumours suggested growth of two primary tumours, one with diploid DNA content and the other with tetraploid DNA content, i.e. a case of neuroblastoma stage 4M (multifocal tumour). However, array CGH (comparative genomic hybridization) data performed on both tumour masses from the patient instead supported a model where a common malignant precursor gave rise to the diploid tumour and subsequently the tetraploid tumour have progressed from the common precursor or by metastasis from the diploid tumour with additional genetic changes. The whole genome dosage analysis showed that the remaining alleles of PHOX2B had been lost in both tumours together with a specific 17q gain pattern. The tetraploid tumour had these features together with additional whole chromosomal loss of chromosomes 3, 9, 14 and 15. Based on the data presented here we suggest that loss of PHOX2B and 17q gain are early events in neuroblastoma tumourigenesis. We also propose investigators to re-analyze the rare cases of multifocal neuroblastomas with the array CGH technique for better understanding of the origin of these tumours.
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PMID:Analysis of neuroblastoma tumour progression; loss of PHOX2B on 4p13 and 17q gain are early events in neuroblastoma tumourigenesis. 1829 34

The homeodomain transcription factors PHOX2A and PHOX2B are vital for development of the autonomic nervous system. Their spatial and temporal expression at the neural crest is instrumental in determining neuronal precursor fate, and by regulating DbetaH expression, the enzyme catalysing noradrenaline synthesis from dopamine, they also play a role in determination of noradrenergic phenotype. Disturbing this finely regulated process leads to disruption of autonomic development and autonomic dysfunction syndromes such as DbetaH deficiency. As it had previously been shown that the catecholamine system is responsive to ELF-EMF, and as this has also been linked to various pathologies and to certain types of cancer, we wondered whether exposure to this type of radiation could affect the expression of PHOX2A, PHOX2B and DbetaH, also during differentiation triggered by retinoic acid. To investigate this possibility we exposed the human SH-SY5Y neuroblastoma cell line to 50 Hz power-line magnetic field at various flux densities and for various exposure times. We measured gene expression in exposed cells compared to control cells and also investigated any changes at protein level. Using our exposure protocol, we found no changes at either transcript or protein level of these important components of the autonomic nervous system and catecholaminergic system.
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PMID:The expression of PHOX2A, PHOX2B and of their target gene dopamine-beta-hydroxylase (DbetaH) is not modified by exposure to extremely-low-frequency electromagnetic field (ELF-EMF) in a human neuronal model. 1857 78

Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.
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PMID:Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. 1892 3

The detection of PHOX2B mutations in a small proportion of patients affected with either familial or sporadic neuroblastoma (NB), has arisen interest on the possible pathogenic role of this gene in the disease determination. In this light, we have carried out a quantitative expression analysis of PHOX2B and its paralogue PHOX2A on a panel of NB cell lines and NB tumour samples to identify a possible differential expression between NB cells and their normal counterpart (adrenal medulla cells). Our results revealed that both PHOX2A and PHOX2B are over-expressed in tumour samples and NB cell lines. Particularly, the expression levels of the two genes in NB cell lines show a highly significant correlation, suggesting their possible synergistic role or a coordinated expression regulation. Furthermore, PHOX2 gene over-expression in NB tumours and cell lines suggests these genes may be widely involved in NB development through either a direct mechanism of up-regulation or a failure in maintaining proper transcript levels after embryonic development.
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PMID:PHOX2A and PHOX2B genes are highly co-expressed in human neuroblastoma. 1894 61

Neuroblastoma (NB), a tumor of the sympathetic nervous system, is the most common solid tumor in childhood. By microarray expression analysis (Affymetrix HU133A) important players in the noradrenalin biosynthesis pathway (DBH, DDC, GATA2, GATA3, PHOX2A, PHOX2B, SLC6A2 SLC18A1 and TH) were found to be among the top ranked genes in showing lower expression in unfavorable NB tumor types as compared to favorable ones. By quantitative PCR with TaqMan, this result was significantly verified for all transcripts (p<0.05, one-tailed) in a new set of 11 primary NB tumors (5 favorable vs. 6 unfavorable). PHOX2A, a downstream target of Phox2b, was found to be the sixth ranked gene from the microarray gene list. Since the PHOX2A gene is localized in a tumor suppressor candidate region at 11q, we screened this gene for mutations by DNA sequencing in 47 tumors of different stages. However, no critical changes were found that could support its role in tumor development or progression. Overall, the findings in this study either suggest that expression of this pathway could be a predictive differentiation marker of NB tumors, or our results could also imply that the noradrenalin biosynthesis pathway is involved in tumor pathogenesis.
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PMID:The Phox2 pathway is differentially expressed in neuroblastoma tumors, but no mutations were found in the candidate tumor suppressor gene PHOX2A. 1921 75

Wilms tumor and neuroblastoma are childhood tumors of the kidney and undifferentiated neural crest cells, respectively. Both disorders are primarily sporadic, but familial Wilms tumor pedigrees and familial neuroblastoma pedigrees are each well recognized and account for approximately 1-3% of each tumor type. Families with Wilms tumor and neuroblastoma in the same, or related individuals, have not been reported. Here, we present nine families with two or more individuals with Wilms tumor and/or neuroblastoma. The affected individuals were otherwise well, without syndromic features. Although this co-occurrence might be due to chance in some families, the coexistence of two rare embryonal tumors in related individuals of multiple families suggests an underlying genetic susceptibility to both tumors. We undertook mutational analysis of the genes known to predispose to non-syndromic familial Wilms tumor (WT1) or neuroblastoma (PHOX2B, ALK) which excluded these as the underlying predisposition genes in the nine families. We also excluded epigenetic and copy-number abnormalities at 11p15 which are known to predispose to embryonal tumors including Wilms tumor and neuroblastoma. Overall, these data suggest that families with both Wilms tumor and neuroblastoma represent a previously unrecognized familial cancer syndrome in which the underlying predisposition gene(s) remain to be determined.
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PMID:A new familial cancer syndrome including predisposition to Wilms tumor and neuroblastoma. 2005 57

Neuroblastoma is a pediatric tumor that is thought to arise from autonomic precursors in the neural crest. Mutations in the PHOX2B gene have been observed in familial and sporadic forms of neuroblastoma and represent the first defined genetic predisposition for neuroblastoma. Here, we address the mechanisms that may underlie this predisposition, comparing the function of wild-type and mutant Phox2b proteins ectopically expressed in proliferating, embryonic sympathetic neurons. Phox2b displays a strong antiproliferative effect, which is lost in all Phox2b neuroblastoma variants analyzed. In contrast, an increase in sympathetic neuron proliferation is elicited by Phox2b variants with mutations in the homeodomain when endogenous Phox2b levels are lowered by siRNA-mediated knockdown to mimic the situation of heterozygous PHOX2B mutations in neuroblastoma. The increased proliferation is blocked by Hand2 knockdown and the antiproliferative Phox2b effects are rescued by Hand2 overexpression, implying Hand2 in Phox2b-mediated proliferation control. A Phox2b variant with a nonsense mutation in the homeodomain elicits, in addition, a decreased expression of characteristic marker genes. Together, these results suggest that PHOX2B mutations predispose to neuroblastoma by increasing proliferation and promoting dedifferentiation of cells in the sympathoadrenergic lineage.
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PMID:Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons. 2008 99

Adrenal neuroblastoma and pheochromocytoma have the same embryonic origin from neural crest cells and mainly arise from the adrenal medulla. Recently, transgenic mice exhibiting tumors in the bilateral adrenal medulla by the expression of SV40 T-antigen were developed. In this study, we investigated mRNA expression in adrenal tumors of transgenic mice and compared them with human pheochromocytoma by DNA microarray analysis. To compare mouse adrenal tumors and human pheochromacytoma, we found that the expressions of noradrenergic neuron-related genes, including dopa decarboxylase, phenylethanolamine-N-methyltransferase and chromogranin B, were up-regulated in humans but not in mice; however, the expression of neuroblastoma-related genes, including Mycn, paired-like homeobox 2b, gamma-aminobutyric acid A receptor beta3 subunit, islet 1 and kinesin family member 1A, was up-regulated in both species. From the gene expression profiles, the characterization of mouse adrenal tumor, may be similar to that of human adrenal neuroblastoma rather than pheochromacytomas. This mouse model would be a useful tool for the development of anti-cancer drugs and for understanding the etiology of adrenal neuroblastoma.
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PMID:Molecular characterization of tumors from a transgenic mouse adrenal tumor model: comparison with human pheochromocytoma. 2066 39

Neuroblastoma, the most frequent solid extracranial tumor of childhood, is characterized by a wide variability of its clinical course. The most important clinical prognostic markers are stage and age at diagnosis, but these markers are insufficient to predict outcome reliably and to determine treatment intensity. Recent evidence indicates that neuroblastoma can be considered as a "genetic disease", firstly by the recent observation that certain alleles of specific genes significantly increase the relative risk to develop neuroblastoma, and the discovery of mutations in genes such as ALK or PHOX2B in rare familial cases. On the other hand, a large number of recurrent genetic somatic alterations have been described in neuroblastoma. Recent technological advances, such as array-CGH (comparative genomic hybridisation), now enable the analysis of these markers in a single step and allow the definition of genomic profiles associated with typical clinical features. Numerical chromosome alterations are observed more frequently in tumors of younger children with localised disease and a good prognosis, whereas segmental chromosome alterations are found more frequently in tumors of older children with advanced stages of disease and a poorer outcome. Future therapeutic stratification schemes can make use of the tumor genomic profile by proposing less intense treatment for infants with a neuroblastoma harboring a favorable tumor genomic profile, while intensifying treatment in case of a defavorable tumor genomic profile. Such approaches require standardisation of the molecular techniques and the interpretation of results for application in international trials.
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PMID:[Genetic alterations in neuroblastoma and their usefulness for clinical management]. 2160 91


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