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)

The human CD44 cell surface glycoprotein has been involved in a variety of functions including lymphocyte homing, extracellular cell matrix attachment, and tumor metastasis. Due to the alternative splicing of the single gene, a large family of different variants or isoforms is generated. Several reports have indicated an up-regulation of CD44 variant (v) isoforms in malignant process, conferring metastatic potential to non-metastatic cells. Neuroblastoma is a tumor characterized by an aggressive and metastatic behavior in advanced stages with amplification of the MYCN protooncogene. In this report we show that the CD44 standard molecule is highly expressed in 100% of stage I-III, IVs neuroblastomas and ganglioneuromas but only in a subset of stage IV tumors. In contrast, no expression of CD44 was detected on MYCN amplified stage IV tumors, thus demonstrating a highly significant negative relationship between MYCN amplification and CD44 expression in neuroblastoma. The expression of CD44 on neuroblastoma cultured cell lines was not shown to be related to MYCN amplification but rather linked to the S-type, schwann/glial differentiation lineage. Immunochemical analysis of tumor samples with anti-CD44v3 and -v6 antibodies and Northern blot analysis of mRNA from cell lines with probes spanning exons 4-10 did not reveal any expression of splice variants on neuroblastomas of all stages and cell lines, thus ruling out a major role of these isoforms in neuroblastoma progression and metastasis.
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PMID:CD44H expression by human neuroblastoma cells: relation to MYCN amplification and lineage differentiation. 751 53

We studied loss of heterozygosity (LOH) on chromosome arm 1p in 108 neuroblastomas using 14 polymorphic DNA markers. One-hundred and four tumors with one or more informative loci; 21 (20%) of the 104 tumors showed LOH on 1p, and were classified into three groups on the basis of interstitial or terminal allelic loss, and presence or absence of LOH on 1p. Seven of the 21 tumors showed an interstitial deletion which encompassed a small region in 1p36 (group A), and the other 14 showed a terminal deletion which encompassed the region from 1pter to 1p32 (group B). Eighty-three tumors without LOH on 1p were classified as group C. The group A patients were mostly less than 12 months of age (6/7), were frequently found by a mass screening program for infants (5/7), had a tumor of non-adrenal origin, and rarely progressed to stage IV (1/7). Most group B patients were 12 months or older (11/14), were found clinically (11/14), had tumors of adrenal origin, and progressed to stage IV (10/14). Analysis of biologic characteristics in group C tumors suggested that they may comprise group A and B tumors. While all group A tumors were in the triploid range (3n) (4/4), most group B tumors were diploid (2n) or tetraploid (4n) (7/10). MYCN amplification was found in 8 group B tumors, but in none of group A tumors. Event-free survivals of groups A, B, and C patients at 3 years were 86, 49, and 74%, respectively (P = 0.0287). These findings suggest that there may be two tumor suppressor genes on 1p which are closely associated with two biologically distinct subtypes of neuroblastoma.
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PMID:There may be two tumor suppressor genes on chromosome arm 1p closely associated with biologically distinct subtypes of neuroblastoma. 751 71

The expression and degree of amplification of the MYCN oncogene in neuroblastoma provide an important indicator of disease prognosis. Detection of MYCN amplification has been described using Southern blotting or polymerase chain reaction (PCR) on DNA from fresh or frozen tissue samples, and using in situ hybridization mainly on metaphase spreads or smears of cultured neuroblastoma cells. In this article, we describe fluorescence in situ hybridization (FISH) results on detection of MYCN amplification in formalin-fixed, paraffin-embedded samples of 25 neuroblastoma and 20 nonneuroblastoma pediatric tumors. MYCN amplification was readily detectable by FISH in eight of the neuroblastomas; correlation with results obtained by Southern analysis was perfect. Of the nonneuroblastoma tumors, only one of three retinoblastoma cases showed MYCN amplification. In contrast to the Southern blot technique, FISH demonstrated the state of amplification heterogeneity of the tumor cells as well as the nature of the amplification units: double-minute chromosomes (DMs) or homogeneously staining regions (HSRs). The results indicate that FISH is a rapid and reliable method for detection of MYCN oncogene amplification in routinely processed samples and may be used to supplant the Southern blot technique.
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PMID:Fluorescence in situ hybridization (FISH) detection of MYCN oncogene amplification in neuroblastoma using paraffin-embedded tissues. 755 Dec 93

We analyzed 156 primary neuroblastoma tumor samples for loss of heterozygosity at the distal short arm of chromosome 1 (1p LOH). We also compared 1p LOH with known clinical and genetic prognostic variables as well as patient outcome. 1p LOH was detected in 30 of 156 tumors (19%) and was strongly associated with adverse clinical and biological features. 1p LOH was also strongly predictive of a poor outcome in univariate analyses (estimated 4-year survival, 32 +/- 10% SE versus 76 +/- 5% SE; P < 0.001). However, the prognostic value of 1p LOH was equivocal when stratified for amplification of the MYCN oncogene (P = 0.16). We conclude that 1p LOH is an important component of a pattern of genetic abnormalities in neuroblastoma associated with an aggressive clinical course.
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PMID:Significance of chromosome 1p loss of heterozygosity in neuroblastoma. 755 46

Neuroblastoma is an embryonal tumour of the sympathetic nervous system with marked heterogeneity in terms of histological maturity and clinical course. A previous study revealed that high tumour levels of the csrc protein, particularly its neuronal isoform (pp60csrcN), correlated with favourable outcome. To test whether this feature reflects a higher degree of neuronal maturation in these tumours, an extended series (47 consecutive neuroblastomas and 10 ganglioneuromas) were analysed for levels of csrc protein isoforms, neuron-specific enolase, and synaptophysin. Immunoblotting and radioimmunoassay techniques were employed. The results were compared with conventional histological signs of neuronal maturation. High pp60csrcN levels were specific for prognostically favourable neuroblastomas and correlated with high neuronal marker levels. However, signs of histological maturation correlated poorly with these parameters. It is therefore concluded that low stage tumours are highly differentiated in biochemical terms despite their frequently immature histology. Furthermore, the clinical usefulness of these biochemical parameters as prognostic markers was compared with established parameters in a multivariate analysis. Stage 4 disease, MYCN amplification, and age above 18 months at diagnosis was the most powerful combination of variables found for predicting a poor outcome. As expected, none of the neuronal differentiation markers investigated could add to the prediction of aggressive disease when compared with this model. However, high expression of pp60csrcN appeared to be useful in predicting long-term survival in high stage infant neuroblastoma.
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PMID:Biochemical evidence for a mature phenotype in morphologically poorly differentiated neuroblastomas with a favourable outcome. 757 41

The human CD44 cell surface glycoprotein has been involved in a variety of functions including lymphocyte homing, extracellular cell matrix attachment and tumour metastasis. A large family of variants or isoforms, generated by alternative splicing of a single gene, has been reported to be involved in the malignant process, by conferring metastatic potential to non-metastatic cells. Neuroblastoma is a tumour characterised by an aggressive and metastatic behaviour in advanced stages, with amplification of the MYCN protooncogene. In this report, we show that the CD44 standard molecule was highly expressed in the majority of tumours of stages 1-3, in all stage 4s and ganglioneuromas, but only in a subset of stage 4 tumours. A lack of CD44 expression was observed in all MYCN amplified stage 4 tumours, thus demonstrating a highly significant inverse relationship between MYCN amplification and CD44 expression in neuroblastoma. In addition, the expression of 4 different CD44 isoforms was measured on all specimens and was always found to be negative. Using neuroblastoma cell lines and MYCN expressing transfectants, we show that CD44 expression by neuroblastoma cell lines is not directly related to MYCN amplification, but is associated to the stage of differentiation or lineage, and to the tumorigenic properties of the cells. In addition, CD44 expression can be upmodulated parallel to differentiation or maturation as induced by retinoic acid, bromodeoxyuridine or phorbol ester. In contrast, cytokines such as IFN gamma, TNF alpha, or growth factors such as bFGF, SCF and TGF beta were ineffective in modulating CD44 expression.
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PMID:CD44 expression and modulation on human neuroblastoma tumours and cell lines. 757 48

Neuroblastomas demonstrate both clinical and biological heterogeneity. We have proposed that neuroblastomas may be classified in three genetically distinct subtypes, based on cytogenetic and molecular analysis. The first comprises those with hyperdiploid or triploid modal karyotypes (or compatible DNA content by flow cytometry), 1p LOH and MYCN amplification are absent, and TRKA expression is high. These patients are likely to be infants with low stages of disease (stages 1, 2, or 4S by the International Neuroblastoma Staging System), and they have a very favourable outcome (> 90% cure). The second group consists of tumours that generally have a near diploid or tetraploid modal chromosome number or DNA content but lack MYCN amplification. They usually have 1p allelic loss, 14q allelic loss or other structural changes, and TRKA expression is usually low. These patients are generally older with advanced stages of disease (stages 3 or 4), and they have a slowly progressive course, with a cure rate of 25-50%. The third group is characterised by tumours with MYCN amplification. These tumours are generally near diploid or tetraploid, with 1p allelic loss, and low or absent TRKA expression. The patients are usually between 1 and 5 years of age with advanced stages of disease, and they have a very poor prognosis (< 5%). It remains to be determined if tumours in one group ever evolve into a less unfavourable group, but current evidence suggests that they are distinct genetically. The identification of the oncogenes, suppressor genes and growth factor receptor pathways involved in neuroblastomas has provided great insight into the mechanisms of malignant transformation and progression, and ultimately they may provide the targets for future therapy.
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PMID:Molecular basis for heterogeneity in human neuroblastomas. 757 54

Neuroblastoma (NB) is a heterogeneous disease. The clinical course may range from spontaneous regression and maturation to very aggressive behaviour. Stage 4s is a unique subcategory of NB, generally associated with good prognosis, despite skin and/or liver involvement and the frequent presence of tumour cells in the bone marrow. Another type of NB is the locally invasive tumour without bone and bone marrow involvement which can also have a good prognosis, irrespective of lymph node involvement. Unfortunately, there is only limited biological information on such tumours which have not been treated with cytotoxic therapy despite lymph node involvement, residual tumour mass after surgery and/or bone marrow infiltration. In order to find specific genetic changes common to NBs with a benign clinical course, we studied the genetic abnormalities of these tumours and compared them with highly aggressive tumours. We analysed a series of 54 localised and stage 4s tumours by means of in situ hybridisation performed on fresh cells or on paraffin embedded tissues. In addition, we performed classical cytogenetics, Southern blotting and PCR analysis on fresh tumour tissue. The majority of patients had been treated with surgery alone, and in a number of patients tumour resection was incomplete. Deletions at 1p36 and amplifications of the MYCN oncogene were absent, and diploidy or tetraploidy were not seen in any case, with residual localised tumours possessing a favourable outcome. Unexpectedly, one patient with a tetraploid 4s tumour without any genetic structural changes not receiving any cytotoxic treatment, did well. Interestingly, this genetic spectrum contrasted with that of progressing tumours, in which most had genetic aberrations, the deletion at 1p36 being the most common event. These data, although limited, suggest that an intact 1p36 (recognised by D1Z2), the absence of MYCN amplification and near-triploidy (at least in localised tumours), represent prerequisites for spontaneous regression and/or maturation.
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PMID:Regression and progression in neuroblastoma. Does genetics predict tumour behaviour? 757 55

The oncogenic activation by amplification of the MYCN gene is frequently observed in human neuroblastomas and occasionally in other tumours with neuronal qualities. As a consequence of amplification, elevated levels of the mycN protein are expressed. mycN contains a C-terminal basic region (BR) that can bind to DNA, and a helix-loop-helix (HLH)-leucine zipper (Zip) domain, which is responsible for the physical interaction with another HLH-Zip protein, max. This principle structure is conserved among all members of the MYC gene family. The resulting dimers can bind to the DNA sequence CACGTG. The mycN protein, but not max, contains, near the N-terminus, a region conferring the ability to activate the transcription of genes. mycN/max heterodimers probably activate and max/max homodimers repress transcription of, as yet, unidentified target genes. In neuroblastoma cells, where mycN is deregulated, the balanced interaction of BR-HLH-Zip proteins is probably perturbed, and, therefore, genes controlled by mycN might be abnormally expressed and thereby alter normal cell growth with the consequence of tumorigenesis.
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PMID:The mycN/max protein complex in neuroblastoma. Short review. 757 56

A comparison of the prognostic impact of five molecular variables in a large series was made, including tests of their nonrandom association and multivariate analysis. Molecular data were available for 377 patients and MYCN amplification, cytogenetic chromosome 1p deletion, loss of chromosome 1p heterozygosity, DNA ploidy and CD44 expression were investigated. Their interdependence and influence on event-free survival was tested uni- and multivariately using Pearson's chi 2-test, Kaplan-Meier estimates, log rank tests and the Cox's regression model. MYCN amplification was present in 18% (58/322) of cases and predicted poorer prognosis in localised (P < 0.001), metastatic (P = 0.002) and even 4S (P = 0.040) disease. CD44 expression was found in 86% (127/148) of cases, and was a marker for favourable outcome in patients with neuroblastoma stages 1-3 (P = 0.003) and 4 (P = 0.017). Chromosome 1p deletion was cytogenetically detected in 51% (28/55), and indicated reduced event-free survival in localised neuroblastoma (P = 0.020). DNA ploidy and loss of heterozygosity on chromosome 1p were of less prognostic value. Most factors of prognostic significance were associated with each other. By multivariate analysis, MYCN was selected as the only relevant factor. Risk estimation of high discriminating power is, therefore, possible for patients with localised and metastatic neuroblastoma using stage and MYCN.
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PMID:Comparison of DNA aneuploidy, chromosome 1 abnormalities, MYCN amplification and CD44 expression as prognostic factors in neuroblastoma. 757 63


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