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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytogenetic and molecular studies in neuroblastoma suggest the presence of a tumour suppressor gene at the distal chromosome band 1p36. Previously, we hypothesised that a constitutional translocation involving the region 1p36 [t(1;17)(p36;q12-q21)] in a patient with neuroblastoma predisposed him to tumour development. Here we report the molecular delineation of the translocation breakpoints. Somatic cell hybrids containing the derivative chromosomes were used to determine the position of chromosome 1p and 17q DNA probes respective to the breakpoints using fluorescence in situ hybridisation. The 1p breakpoint was localised between the PND and D1S56 loci. The chromosome 17q breakpoint is flanked by NF1 and SCYA7, as proximal and distal marker, respectively. We redefined the translocation as t(1;17)(p36.31-13;q11.2-q12). The identification of flanking markers of the breakpoints is a prerequisite for breakpoint cloning and identification of a putative neuroblastoma suppressor gene.
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PMID:Characterisation of the chromosome breakpoints in a patient with a constitutional translocation t(1;17)(p36.31-p36.13;q11.2-q12) and neuroblastoma. 757 58

Previous reports on possible genomic imprinting of the neuroblastoma tumour suppressor gene on chromosome 1p36 have been conflicting. Here we report on the parental origin of 1p36 alleles lost in 47 neuroblastomas and on a detailed Southern blot analysis of the extent of the 1p deletions in 38 cases. The results are remarkably different for tumours with and without N-myc amplification. In the N-myc single copy tumours we show that the lost 1p36 alleles are of preferential maternal origin (16 of 17 cases) and that the commonly deleted region maps to 1p36.2-3. In contrast, all N-myc amplified neuroblastomas have larger 1p deletions, extending from the telomere to at least 1p35-36.1. These deletions are of random parental origin (18 of 30 maternal LOH). This strongly suggests that different suppressor genes on 1p are inactivated in these two types of neuroblastoma. Deletion of a more proximal suppressor gene is associated with N-myc amplification, while a distal, probably imprinted, suppressor can be deleted in N-myc single copy cases.
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PMID:Evidence for two tumour suppressor loci on chromosomal bands 1p35-36 involved in neuroblastoma: one probably imprinted, another associated with N-myc amplification. 763 1

p58cdc2L1, a protein kinase implicated in apoptotic signaling, is one of eight separate kinases encoded by three tandemly duplicated and linked genes, which we have termed PITSLRE A, B and C. One allele of this complex on chromosome 1 was either deleted or translocated in each of 18 neuroblastoma cell lines with cytogenetically apparent 1p alterations. A protein encoded by this locus, PITSLRE gamma 1, was absent in three of the lines and a smaller, apparently truncated, PITSLRE polypeptide was found in another line. These findings identify a novel gene complex on chromosome 1 that encodes a protein kinase subfamily. We suggest that the PITSLRE locus may harbour one or more tumour suppressor genes affected by chromosome 1p36 modifications in neuroblastoma.
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PMID:Alterations in the PITSLRE protein kinase gene complex on chromosome 1p36 in childhood neuroblastoma. 792 Jun 54

We are studying the biological activity and regulation of mammalian Ras protein in tumours and in physiological signalling. We have shown that GAP (the GTPase-activating protein) is a potent negative regulator of normal Ras in cells. Reduction or loss of the NF1 gene product neurofibromin, in association with genetic abnormalities of the NF1 locus, has been identified in schwannoma cell lines from patients with neurofibromatosis and in melanoma and neuroblastoma lines from patients without neurofibromatosis. Although loss of neurofibromin in the schwannoma lines was associated with a high proportion of normal Ras protein in the active GTP-bound state, Ras-GTP appeared to be appropriately regulated in the melanoma and neuroblastoma lines, which contain normal levels of GAP. Therefore the GTPase-activating activity of neurofibromin is not essential for negative regulation of Ras in some cell types and the putative tumour suppressor function of neurofibromin in such cell types is independent of its GTPase-activating activity. Mitogen activation of Ras in fibroblasts is mediated primarily by exchange factors, which probably interact with a region on the Ras protein distinct from the region required for interaction with GAP. Multiple full-length cDNAs have identified a mouse gene whose products are related to yeast CDC25 guanine nucleotide exchange factor.
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PMID:Cell transformation by ras and regulation of its protein product. 829 27

Chromosomal band 1p36 probably harbours several neuroblastoma suppressor genes. A neuroblastoma patient has been described with a constitutional balanced translocation, t(1;17)(p36;q12-21). Cytogenetically, no loss of chromosomal material was visible. The 1p36 translocation breakpoint could therefore have inactivated one allele of a tumour suppressor gene, thus predisposing the patient to develop neuroblastoma. We localized this breakpoint by pulsed field gel electrophoresis, analysis of yeast artificial chromosomes, and fluorescence in situ hybridization. Here we report that the breakpoint is within a large cluster of small nuclear RNA U1 (RNU1) and some tRNA genes (TRE, TRN) on chromosomal band 1p36. The size of this cluster is over two megabases and it contains many other locally repeated sequences. Polyadenylated transcripts were identified for some of these sequences. In addition, the cluster is the target for integration of an adenovirus 5/SV40 hybrid virus. The translocation breakpoint maps distal of this viral integration site and proximal of marker PND.
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PMID:Balanced translocation in a neuroblastoma patient disrupts a cluster of small nuclear RNA U1 and tRNA genes in chromosomal band 1p36. 852 82

Neuroblastoma is a childhood neural crest tumour, genetically characterized by frequent deletions of the short arm of chromosome 1 and amplification of N-myc. Here we report the first evidence for a neuroblastoma tumour suppressor locus on 4pter. Cytogenetically we demonstrated rearrangements of 4p in 7 out of 26 evaluable tumours (27%). Subsequent analysis of loss of heterozygosity (LOH) by Southern blotting revealed allelic loss of 4p in 16/82 (19.5%) informative neuroblastomas. Taken together cytogenetic and Southern blot analyses showed loss of 4p in 20/86 neuroblastomas analysed (23%). The common deleted region was bordered by the probe D4S123 and encompassed the distal 34 cM of 4p. We found no evidence for genomic imprinting of the 4p locus as the 4p alleles lost in the tumours were of random maternal and paternal origin. LOH4p was found at all disease stages and in every age group. Furthermore LOH4p was present both in cases with and without LOH1p and amplification of N-myc.
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PMID:Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel tumour suppressor gene locus. 864 6

Using a new strategy for tumour suppressor gene isolation based on subtractive hybridization and the subsequent selection of transforming 'genetic suppressor elements', we have cloned a novel gene called ING1 encoding a 33-kD protein (p33ING1) that displays characteristics of a tumour suppressor. Acute expression of transfected constructs encoding this gene inhibited cell growth while chronic expression of ING1 antisense constructs promoted cell transformation. Limited analyses of tumour cell lines show that mutation of the ING1 gene occurs in neuroblastoma cells and reduced expression was seen in some breast cancer cell lines. These results demonstrate that ING1 can act as a potent growth regulator in normal and in established cells and provide evidence for a role as a candidate tumour suppressor gene whose inactivation may contribute to the development of cancers.
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PMID:Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation. 894 21

The adenomatous polyposis coli tumour suppressor protein is highly expressed in developing rodent brain, but its function is unclear. Recent studies have suggested a role for this protein in regulating microtubule dynamics. Neuro 2A mouse neuroblastoma cells were previously thought not to express this protein. Using immunochemical techniques, this report corrects this observation. Immunoreactive bands of a size consistent with that of the full-length protein were observed by western blotting. Using immunocytochemistry, punctate immunoreactivity localized to areas of the cell containing microtubules, particularly neurite growth cones, in a distribution suggesting a role in neuritogenesis and growth cone extension. The protein did not localize to actin-rich cellular structures, and perturbation of the actin cytoskeleton had no effect upon this distribution. Treatment of cells with taxol to stabilize microtubules caused the concentration of the immunoreactive puncta to the tips of microtubules and areas along the axis of potential microtubule assembly. Treatment of cells with the microtubule disrupting reagent nocodazole showed that over shorter times the punctate distribution was not dependent upon polymerized microtubules. However, at longer incubation times a decrease in punctate immunostaining was observed. These results indicate that the intracellular distribution of the adenomatous polyposis coli protein is dependent upon microtubule but not actin dynamics. A role for this protein in the regulation of directed microtubule assembly is suggested.
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PMID:The cellular distribution of the adenomatous polyposis coli tumour suppressor protein in neuroblastoma cells is regulated by microtubule dynamics. 930 Apr 41

Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes.
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PMID:Molecular genetic analysis of familial neuroblastoma. 951 25

Cellular, cytogenetic, and molecular evidence indicates that chromosome band 1p36 is often deleted in neuroblastoma cell lines and tumours, suggesting the presence of one or more tumour suppressor genes in this region. We used a multifaceted approach to analyse the commonly deleted region, 28 distal 1p-specific polymorphic loci were used to detect loss of heterozygosity (LOH) in a panel of primary neuroblastoma tumours. Thirty-two of 122 tumours (26%) demonstrated LOH at three or more loci. In addition, a patient with a constitutional deletion of 1p36.2-.3 and two neuroblastoma cell lines with 1p36 abnormalities were characterised by FISH. When combined with the LOH data, a single consensus region of deletion was defined proximally by PLOD and distally by D1S80, a region spanning approximately five megabases. Several proposed candidate tumour suppressor genes, including ID3, CDC2L1, DAN, PAX7, E2F2, TNFR2 and TCEB3, map outside of this region; however, the transcription factor HKR3 cannot be excluded. LOH for 1p is correlated with adverse clinical and biological features and a poor prognosis, but 1p LOH is not an independent predictor of overall survival. To identify additional candidate genes, an integrated physical map of 1p35-36 is being constructed. The current map includes 445 polymerase chain reaction (PCR)-formatted markers and 608 YACs. This map will help identify region-specific transcripts by direct selection and sequencing.
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PMID:Molecular analysis of the region of distal 1p commonly deleted in neuroblastoma. 951 32


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