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)

Mutations of CDKN2 have been found recently in melanoma and many other tumor types. Neuroblastoma shares with melanoma a neuroectodermal origin and a high incidence of deletions of the short arm of chromosome 1. Therefore, we analyzed 18 primary neuroblastomas and 9 tumor-derived cell lines for mutations in CDKN2. We used PCR-single-strand conformation polymorphism to examine exons 1 and 2 of the CDKN2 gene for mutations, but none were detected. Furthermore, no homozygous deletions were detected and there was no loss of heterozygosity at the closely linked IFNA locus. We conclude that disruption of the CDKN2 gene is not required for malignant transformation of human neuroblastomas.
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PMID:No CDKN2 mutations in neuroblastomas. 774 1

Neuroblastoma is one of the most frequent tumors in infancy. We analyzed 26 neuroblastomas, two ganglioneuromas, and a neuroblastoma metastasis for mutations and homozygous deletions of the p16 (or MTS1 or CDKN2) gene by means of the polymerase chain reaction (PCR) in combination with the single-strand conformation polymorphism (SSCP) technique and by multiplex PCR analysis. We detected mobility shifts in the SSCP gels in seven cases in the 3 half of exon 2 (named exon 2C) of the p16 gene. By PCR amplification of this particular region and SacII restriction enzyme digestion, we confirmed that those cases had a known polymorphism at codon 140 of the p16 gene. Neither mutations nor homozygous deletions were detected. Our results confirm those of Beltinger et al. (Cancer Res 55:2053-2055, 1995), which showed no p16 mutations or homozygous deletions in 18 primary neuroblastomas and nine tumor-derived cell lines. We conclude that the common pattern of p16 inactivation by homozygous deletion or mutation does not seem to be relevant to the development of neuroblastomas.
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PMID:Mutational analysis of the p16 gene in human neuroblastomas. 911 82

The genes responsible for the development of neuroblastoma following in vivo deletion or mutation are largely unknown. We have performed loss of heterozygosity studies on a series of 24 Portuguese primary neuroblastomas using 6 polymorphic markers located at chromosome 9p21 spanning the p16/MTS1/CDKN2, p15/MTS2/CDKN2B, and the interferon alpha and beta genes. Loss of heterozygosity was observed in 4 of the 24 tumors (17%), a somewhat lower percentage than a previous study that identified patients by a mass screening program. A correlation was also observed between 9p21 LOH and 1p36 LOH in our group of tumors. Two distinct regions of 9p21 deletion were observed: one located in the region adjacent to the markers D9S162 and D9S1747 and a second located centromerically of the p16 gene near the D9S171 marker. The latter region is exclusive of the p16 gene. This result suggests the presence of at least one other tumor suppressor gene at 9p21, apart from the p16 and p15 genes, which may be of importance to the development of neuroblastoma.
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PMID:Loss of heterozygosity at chromosome 9p21 in primary neuroblastomas: evidence for two deleted regions. 921 21

Loss of heterozygosity of several specific genomic regions is frequently observed in neuroblastoma tumors and cell lines, but homozygous deletion (HD) is rare, and no neuroblastoma tumor suppressor gene (TSG) has yet been identified. We performed a systematic search for HD, indicative of a disrupted TSG, in a panel of 46 neuroblastoma cell lines. An initial search focused on a well-characterized consensus region of hemizygous deletion at 1p36.3, which occurs in 35% of primary neuroblastomas. Each cell line was screened with 162 1p36 markers, for a resolution of 13 kb within the consensus 1p36.3 deletion region and 350 kb throughout the remainder of 1p36. No HDs were detected. This approach was expanded to survey 21 known TSGs, specifically targeting intragenic regions frequently inactivated in other malignancies. HD was detected only at the CDKN2A (p16INK4a/p14ARF) gene at 9p21 and was observed in 4 of 46 cell lines. The observed region of HD included all exons of both CDKN2A and the closely linked CDKN2B (p15INK4b) gene for cell lines LA-N-6 and CHLA-174, all exons of CDKN2A but none of CDKN2B for CHLA-179, and only 104 bp within CDKN2A exon 2 for CHLA-101. All four deletions are predicted to inactivate the coding regions of both p16INK4a and p14ARF. HD was observed in corresponding primary tumor samples for CHLA-101 and CHLA-174 but was not present in constitutional samples. These results suggest that for neuroblastoma, large HDs do not occur within 1p36, most known TSGs are not homozygously deleted, and biallelic inactivation of CDKN2A may contribute to tumorigenicity in a subset of cases.
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PMID:Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma. 1121 68

Ewing tumour is characterized by specific chromosome translocations which fuse EWS to a subset of genes encoding ETS transcription factors, most frequently FLI-1. We report the analysis of the expression of various cell cycle regulators both in Ewing tumour derived cell lines and in different cellular models with either inducible or constitutive EWS-FLI-1 cDNA expression. In Ewing cell lines, cyclin D1, CDK4, Rb, p27KIP1 and c-Myc were consistently highly expressed whereas p57KIP2, p15INK4B and p14ARF demonstrated undetectable or low expression levels. The amount of p16INK4A, p21CIP1, p18INKAC and CDK6 was variable from one cell line to the other. The inducible expression of EWS-FLI-1 led to a strong upregulation of c-Myc and a considerable downregulation of p57KIP2. Other proteins did not show evident modification. High c-Myc and very low p57KIP2 expression levels were also observed in neuroblastoma NGP cells constitutively expressing EWS-FLI-1 as compared to parental cells. Analysis of the p57KIP2 promoter indicated that EWS-FLI-1 downregulates, possibly through an indirect mechanism, the transcription of this gene. Finally, we show that ectopic expression of p57KIP2 in Ewing cells blocks proliferation through a complete G1 arrest. These results suggest that the modulation of p57(KIP2) expression by EWS-FLI-1 is a fundamental step in Ewing tumorigenesis.
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PMID:Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2and c-Myc expression. 1142 75

Expression of the p16INK4A (p16), p15INK4B (p15), and p14ARF genes, located at 9p21, was examined in pediatric neuroblastoma (NB), Ewing's sarcoma (ES), and rhabdomyosarcoma (RMS). p16 expression was absent in 4 of 5 ESs, and 2 of these 4 cases died. p16 expression was reduced or absent in 10 of 12 RMSs, and 4 of these 10 cases died. These results suggested the possibility that p16 expression was associated with the progression of ES and RMS. There has been no previous report on p14ARF in NB. Our investigation might indicate that abnormal expression of the p16 and p14ARF was associated with a poor prognosis in NB, although in some cases of NB normal p16 and abnormal p14ARF expression was seen. These findings suggest an important role of p14ARF gene in the tumorigenesis of NB. The different incidence of expression of the p16, p15, and p14ARF genes in these 3 tumor types may reflect differences of the molecular process through which the 3 tumors develop. Our results suggest that abnormal expression of the p16 and/or p14ARF may be associated with a poor prognosis in these 3 tumors.
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PMID:Aberrations of p16INK4A, p14ARF and p15INK4B genes in pediatric solid tumors. 1296 98

Chromosome 9p21 is frequently deleted in many cancers. Previous reports have indicated that 9p21 LOH is an uncommon finding in neuroblastoma (NB), a tumour of childhood. We have performed an extensive analysis of 9p21 and genes located in this region (cyclin-dependent kinase inhibitor 2A - CDKN2A/p16(INK4a), CDKN2A/p14(ARF), CDKN2B/p15(INK4b), MTAP, interferon alpha and beta cluster). LOH was detected in 16.4% of 177 NB. The SRO was identified between markers D9S1751 and D9S254, at 9p21-23, a region telomeric to the CDKN2A and MTAP genes. A significantly better overall and progression-free survival was detected in stage 4 patients displaying 9p21-23 LOH. Hemizygous deletion of the region harbouring the CDKN2A and CDKN2B loci was identified in two tumours by means of fluorescent in situ hybridisation and MTAP was present by immunostaining in all but one tumour analysed. The transcriptional profile of tumours with 9p21-23 LOH was compared to that of NB displaying normal 9p21-23 status by means of oligonucleotide microarrays. Four of the 363 probe sets downregulated in tumours with 9p21-23 LOH were encoded by genes mapping to 9p22-24. The only well-characterised transcript among them was nuclear factor I-B3. Our results suggest a role for genes located telomeric of 9p21 in good risk NB.
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PMID:Comprehensive analysis of the 9p21 region in neuroblastoma suggests a role for genes mapping to 9p21-23 in the biology of favourable stage 4 tumours. 1530 92

The genetic instability driving tumorigenesis is fueled by DNA damage and by errors made by the DNA replication. Upon DNA damage the cell organizes an integrated response not only by the classical DNA repair mechanisms but also involving mechanisms of replication, transcription, chromatin structure dynamics, cell cycle progression, and apoptosis. In the present study, we investigated the role of p19INK4d in the response driven by neuroblastoma cells against DNA injury caused by UV irradiation. We show that p19INK4d is the only INK4 protein whose expression is induced by UV light in neuroblastoma cells. Furthermore, p19INK4d translocation from cytoplasm to nucleus is observed after UV irradiation. Ectopic expression of p19INK4d clearly reduces the UV-induced apoptosis as well as enhances the cellular ability to repair the damaged DNA. It is clearly shown that DNA repair is the main target of p19INK4d effect and that diminished apoptosis is a downstream event. Importantly, experiments performed with CDK4 mutants suggest that these p19INK4d effects would be independent of its role as a cell cycle checkpoint gene. The results presented herein uncover a new role of p19INK4d as regulator of DNA-damage-induced apoptosis and suggest that it protects cells from undergoing apoptosis by allowing a more efficient DNA repair. We propose that, in addition to its role as cell cycle inhibitor, p19INK4d is involved in maintenance of DNA integrity and, therefore, would contribute to cancer prevention.
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PMID:Induction of p19INK4d in response to ultraviolet light improves DNA repair and confers resistance to apoptosis in neuroblastoma cells. 1575 Jun 20

The regulation of D-type cyclin-dependent kinase activity is critical for neuronal differentiation and apoptosis. We recently showed that cyclin D1 is sequestered in the cytoplasm and that its nuclear localization induces apoptosis in postmitotic primary neurons. Here, we further investigated the role of the subcellular localization of cyclin D1 in cell cycle withdrawal during the differentiation of N1E-115 neuroblastoma cells. We show that cyclin D1 became predominantly cytoplasmic after differentiation. Targeting cyclin D1 expression to the nucleus induced phosphorylation of Rb and cdk2 kinase activity. Furthermore, cyclin D1 nuclear localization promoted differentiated N1E-115 cells to reenter the cell cycle, a process that was inhibited by p16(INK4a), a specific inhibitor of D-type cyclin activity. These results indicate that cytoplasmic sequestration of cyclin D1 plays a role in neuronal cell cycle withdrawal, and suggests that the abrogation of machinery involved in monitoring aberrant nuclear cyclin D1 activity contributes to neuronal tumorigenesis.
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PMID:Cytoplasmic sequestration of cyclin D1 associated with cell cycle withdrawal of neuroblastoma cells. 1636 55

Mutations in the CDKN2A gene underlie melanoma susceptibility in as many as 50% of melanoma kindreds in selected populations, and several CDKN2A founder mutations have been described. Inherited mutations in CDKN2A have been found to be associated with other, non-melanoma cancers including pancreatic cancer (PC) and neural system tumors (NST). Here we report a novel germline mutation in exon 1 of the CDKN2A gene, E27X, which we first detected in melanoma patients living in or originally from a small geographic area bordering Liguria in north-western Italy. A subset of melanoma kindreds positive for this mutation displayed PC and neuroblastoma. E27X generates a premature stop codon, leading to dramatically reduced protein levels of p16 and leaving p14ARF unaltered. As PC and NSTs have been postulated to be preferentially associated with CDKN2A mutations located in exon 2 and/or affecting p14ARF alone, the position of E27X in exon 1alpha provides interesting insights towards clarifying the mechanisms by which the CDKN2A/ARF locus is involved in cancer predisposition.
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PMID:Impact of E27X, a novel CDKN2A germ line mutation, on p16 and p14ARF expression in Italian melanoma families displaying pancreatic cancer and neuroblastoma. 1689 9


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