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

DEAD box proteins are putative RNA helicases that have been implicated in cellular processes involving alteration of RNA secondary structure, such as translation initiation and splicing. These proteins share eight conserved amino acid motifs, including Asp(D)-Glu-(E)-Ala(A)-Asp(D) which is part of a more extended motif. Recently, we have shown that the novel DDX1 gene containing a DEAD box motif maps to the same chromosome band as MYCN at 2p24 and is co-amplified with MYCN in retinoblastoma cell lines. Here, we show that the DDX1 gene is co-amplified with the MYCN gene in 2 of three neuroblastoma cell lines and that DDX1 RNA levels correlate with DDX1 gene copy number. Since amplification of MYCN is an indicator of poor prognosis in neuroblastoma, it was of interest to determine whether co-amplification with DDX1 occurred in clinical samples of neuroblastoma and whether such a finding carried any additional prognostic significance. We determined the gene copy number of DDX1 in 32 neuroblastoma patient samples (representative of all stages): 13 were MYCN amplified and 19 had normal copy numbers of the MYCN gene. Of the 13 neuroblastomas that were MYCN amplified, seven were also DDX1 amplified. Of the 19 that were not MYCN amplified, none were DDX1 amplified. This is the first example of a gene that is co-amplified with MYCN at a high frequency in neuroblastoma. While there was a trend towards a worse clinical outcome with co-amplification, the numbers were too small to reach significance.
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PMID:Co-amplification of MYCN and a DEAD box gene (DDX1) in primary neuroblastoma. 773 93

Amplification of the oncogene MYCN is a genetic change frequently observed in neuroblastoma and is an indicator of poor prognosis. MYCN copy number is currently determined by Southern blot hybridization. This technique takes 2 to 3 weeks, is labor-intensive, is sensitive to DNA degradation, and requires large quantities of DNA. We have evaluated a new, semiquantitative method of estimating gene copy number that uses differential polymerase chain reaction (PCR). The procedure can be performed in 1 day, is highly reproducible, and requires only nanogram quantities of DNA. It employs a semiquantitative, nonisotopic PCR technique based on differential competition for PCR substrates. MYCN gene primers are amplified together with primers from a single-copy internal control gene. Following electrophoretic separation, the ratio of the two PCR products is determined visually and by densitometric analysis of ethidium bromide-stained agarose gels. This differential ratio is then compared to a series of ratios generated from standards of known MYCN gene copy number. We compared the results obtained by this differential PCR method with those obtained by conventional Southern blotting in 16 cases of primary neuroblastoma. All amplified tumors were detected by differential PCR, and no false positives were observed. We confirmed that differential PCR is a rapid and reliable alternative to Southern blotting for MYCN copy number assessment and is highly suited to the analysis of DNA derived from needle biopsies.
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PMID:Assessment of MYCN amplification in neuroblastoma biopsies by differential polymerase chain reaction. 780 81

Although pediatric solid tumors are cytogenetically less well characterized than childhood leukemias, an understanding of the role of chromosomal changes in the development of these neoplasms is emerging. The major clinical importance of chromosome analysis today is diagnostic. Especially in small cell round cell tumors of childhood, the unique karyotypic patterns that characterize some of the differential diagnostic entities make it possible to determine with a high degree of certainty which type of cancer the child has. Molecular studies have revealed that almost all retinoblastomas show homozygous loss of function of the RB1 gene in 13q14. At the cytogenetic level, however, aberrations of 13q are seen in less than 25% of retinoblastomas; instead, the presumably progression-related i(6p) and aberrations leading to gain of 1q predominate, each being present in one-third of the tumors. Twenty percent of cytogenetically aberrant Wilms' tumors show structural rearrangements, often deletions, of 11p13 and 11p15, where the WT1 and WT2 genes map. Other frequent changes are trisomy 12 and duplication of 1q. The most common (80%) cytogenetic abnormality in neuroblastoma is loss of distal 1p, a chromosome segment thought to harbor at least two tumor-suppressor genes of importance in tumorigenesis. Double minute chromosomes or homogeneously staining regions are present in one-third of all neuroblastomas and are associated with MYCN amplification. Loss of 1p material or MYCN amplification predicts a poor outcome. The most common (30%) chromosomal aberration in primitive neuroectodermal tumors of the central nervous system is i(17q). The formation of this isochromosome may help inactivate a tumor-suppressor gene located distal to the TP53 locus on 17p. No specific chromosome abnormality has been detected in gliomas, but monosomy 22 and rearrangements leading to loss of 1p and gain of 1q are recurrent. Few hepatoblastomas with chromosomal changes have been reported, but several potential primary aberrations have been described, including +2, +20, and duplication 8q. In Ewing's sarcoma, t(11;22)(q24;q12) is the primary aberration, with trisomy 8 and gain of 1q being frequent secondary changes. Fibrosarcomas in children often carry only numeric aberrations, especially trisomy for chromosomes 11, 20, 17, and 8. Most osteosarcomas are cytogenetically complex, and no specific abnormality has been detected; the single most common change is loss of chromosome 13, which is observed in half the tumors. In contrast, the low-malignancy parosteal osteosarcomas often display supernumerary ring chromosomes as the sole karyotypic deviation. The cytogenetic profiles of rhabdomyosarcomas differ among the various morphologic subtypes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytogenetic analysis in the examination of solid tumors in children. 794 9

Of 567 children with neuroblastoma diagnosed between November 1984 and May 1993 in 21 Italian institutions, 235 (41%) have been evaluated for MYCN oncogene amplification. The amplification (3 or more copies of the gene) was found in 39 patients (17%) and was more frequent in patients aged more than one year, abdominal primary site of the tumor, advanced stages, normal urinary excretion of vanillylmandelic acid (VMA), and high level of LDH, NSE and ferritin. The five-year survival of the 235 patients (62%) was significantly better in patients with normal copy number of MYCN (69% versus 29%). By correlating genomic amplification with clinical and biochemical characteristics, MYCN amplification was found associated with a worse prognosis even when patients were subdivided for age (under and above one year), disease extension (localized operable, localized but inoperable, and disseminated) with exception for Stage IV-S, VMA and homovanillic acid excretion, serum levels of NSE and ferritin, but not of LDH. These data confirm the unfavourable prognostic meaning of MYCN amplification, but are unable to define if it represents a new independent variable.
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PMID:[The prognostic effect of amplification of the MYCN oncogene in neuroblastoma. The preliminary results of the Italian Cooperative Group for Neuroblastoma (GCINB)]. 797 42

The prognostic value of the MDR1 gene expression in neuroblastoma (NB) was assessed in a multivariate analysis performed in a series of 84 patients (pts) taking into account the main known clinical and biological factors of the disease, i.e., age, stage, MYCN genomic content and DNA ploidy index. Twenty seven children were < 1 year (yr), 13 presented with stage I and II, 7 with stage IV-S, 17 with stage III and 47 (56%) with stage IV. Tumor specimens were obtained from involved bone marrow (n = 12) or surgical primary tumor specimens (n = 72). MDR1 gene expression was measured by Northern hybridization technique and expressed in arbitrary units (a. u.) (Goldstein et al., 1989). Analysis of MYCN genomic content and DNA ploidy index were performed by Southern blot hybridization technique and flow cytometry, respectively. Out of 84 tumor specimens 19 (23%) showed MYCN amplification (> 3 copies/haploid genome). In 24 cases (29%) no detectable MDR1 gene transcript was found (0 a.u.) whereas 42 (50%) had a value in the range 1-30 a.u., and 18 (21%) a value beyond 30 a.u.. High transcript levels were found in localized as well as in metastatic NB (NS). No significant correlation between MDR1 gene expression, age, stage, or MYCN genomic content was found In univariate analysis stage IV, age > 1 yr, MYCN amplification, diploid DNA content and high MDR1 gene transcript levels were significantly related to an increased risk of death. In multivariate analysis only stage IV, MYCN amplification and MDR1 overexpression remained significantly associated with an increased risk of death.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prognostic value of MDR1 gene expression in neuroblastoma: results of a multivariate analysis. 797 2

In metastatic human neuroblastoma, MYCN amplification and MDR1 overexpression are frequently observed. No in vivo model is yet available for the study of the regulation of these two genes during the metastatic process of this disease. Culture of an involved bone marrow of a patient with stage IV neuroblastoma gave rise to an established in vitro neuroblastoma cell line, IGR-N-91, and a subsequent s.c. xenograft model in nude mice. When cultured in vitro, blood cells, bone marrow, and the myocardium of mice bearing s.c. tumor xenograft reproducibly yielded cells with morphological and molecular features of neuroblastoma cells, including consistent MYCN amplification (60 copies/haploid genome). Compared to the neuroblastoma cells of the primitive s.c. tumor xenograft, metastatic cells showed a significant increase in the MYCN gene transcript levels associated with an overexpression of the MDR1 gene mRNA levels leading to a P-glycoprotein capable of extruding Adriamycin. This study offers compelling evidence that (a) IGR-N-91 is a human neuroblastoma xenograft model able to induce metastasis in nude mice, (b) an increase in MYCN and MDR1 transcripts levels is associated with the metastatic process, and (c) IGR-N-91 provides a biological tool for the study of gene activations during tumor dissemination in neuroblastoma.
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PMID:Coactivation of the MDR1 and MYCN genes in human neuroblastoma cells during the metastatic process in the nude mouse. 817 36

Amplification of the human N-myc protooncogene, MYCN, is frequently seen either in extrachromosomal double minutes or in homogeneously staining regions of aggressively growing neuroblastomas. MYCN maps to chromosome 2 band p23-24, but homogeneously staining regions have never been observed at this band, suggesting transposition of MYCN during amplification. We have employed fluorescence in situ hybridization to determine the status of MYCN at 2p23-24 in five human neuroblastoma cell lines. All five lines carried, in addition to amplified MYCN in homogeneously staining regions or double minutes, single-copy MYCN at the normal position. In one line there was coamplification of MYCN together with DNA of the host chromosome 12, to which MYCN had been transposed. Our results suggest a model of amplification where MYCN is retained at its original location. They further sustain the view that either the initial events of MYCN amplification or the further evolution of amplified MYCN copies follow mechanisms different from those leading to amplification of drug-resistance genes.
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PMID:MYCN is retained in single copy at chromosome 2 band p23-24 during amplification in human neuroblastoma cells. 820 21

We encountered a case of abdominal primary stage IV neuroblastoma which recurred in the central nervous system. A neuroblastoma cell line, designated KP-N-NS, was established from this brain metastatic lesion. This is considered to be the first neuroblastoma cell line established from a brain metastatic lesion. In culture, KP-N-NS exhibited N(neuroblastic) type cell morphology with neurite-like processes and small cell bodies. This cell line revealed karyotypic abnormality, 46, XX, -1, +der (1)t(1;?)(p36.1;?), and twelve-fold amplification of MYCN DNA (twice as much in primary bone marrow tumor cells). Integrin study indicated high expression levels of alpha 1 beta 1 and alpha 4 beta 1, but alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha 6 beta 1, alpha 6 beta 4, and alpha v beta 3 were barely detectable by fluorescence-activated cell sorting (FACS) analysis. Compared with 8 other previously established N-type neuroblastoma cell lines, no significantly characteristic integrin expression was detected in this cell line. KP-N-NS will provide a useful tool for the study of metastasis and relapse in the central nervous system in neuroblastoma patients.
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PMID:Establishment and characterization of a human neuroblastoma cell line derived from a brain metastatic lesion. 829 18

A method is described to estimate MYCN (N-myc) oncogene amplification in neuroblastoma by the technique of differential polymerase chain reaction (PCR). The technique is quicker than conventional Southern blotting techniques and does not require radioactive materials. The ability to measure MYCN amplification from smaller amounts of tumor DNA also permits measurement from Tru-cut biopsy samples and opens the possibility of retrospective measurement of MYCN status from single paraffin sections of archival material.
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PMID:MYCN amplification by differential PCR. 844 50

Neuroblastoma (NB) is a paediatric tumour showing an appreciable variability in clinical evolution. Localised tumours (especially stage 1) can be mildly treated with good success while metastatic tumours (stage 4) are highly aggressive. This suggests a great biological diversity. In fact, molecular and genetic studies have revealed distinct abnormalities in localised and non-localised tumours. Loss of heterozygosity for the short arm of chromosome 1, 1p deletion, and MYCN amplification are present in stages 3 and 4 but rarely in stages 1 and 2. Metastatic stage 4S in infants is peculiar and does not show the same genetic and molecular abnormalities found in advanced metastatic tumours. Considering the biological alterations associated with NB, it would appear that advanced stage NB conforms to the multistep model of tumour development while stage 4S can be divided into two groups: one arising from a lack of cellular differentiation and the other as a consequence of an additional 'one hit' mutation.
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PMID:Neuroblastoma: a multiple biological disease. 848 68


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