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PubMed2002

MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group.

CONTEXT: Brain tumors are the most common solid tumor in childhood, and medulloblastoma is the most common malignant brain tumor in this age group. Cytogenetic abnormalities that have been described in childhood medulloblastoma include loss of 17p, amplification of MYCC (c-myc), amplification of MYCN (N-myc), and isochromosome 17q. Data on these tumors indicate that the frequency of MYCC amplification is 5% to 10%. Fluorescence in situ hybridization is a powerful tool for investigating these features on archival material. OBJECTIVES: To determine if intratumoral heterogeneity exists for MYCC and MYCN in medulloblastomas and if tumors with amplified MYCC or MYCN exhibit consistent histologic patterns. DESIGN: In this fluorescence in situ hybridization study, we investigated the frequency and prognostic significance of MYCC and MYCN amplification in 77 medulloblastomas derived from the Children's Oncology Group. RESULTS: MYCC amplification occurred in only 4 (5.2%) of 77 tumors. The 4 patients died of clinically aggressive neoplasms within 7 months of diagnosis. Similarly, 4 of 77 patients' tumors were found to exhibit MYCN amplification, but survival data are incomplete at present, therefore prognostic significance cannot be characterized. CONCLUSIONS: These data establish the frequency of MYCC amplification in a large cohort of children with medulloblastoma and further suggest that MYCC amplification may be a marker of poor prognosis. Intratumoral heterogeneity was identified for these oncogenes in that 1 patient's tumor exhibited evidence of both MYCN and MYCC amplification, and this patient experienced a shortened survival time.

Adolescent↗

PubMed1999

The use of fine-needle aspiration cytology in the molecular characterization of neuroblastoma in children.

BACKGROUND: The utility of fine-needle aspiration (FNA) material in the molecular characterization of a group of neuroblastic tumors (NT) in children is presented. METHODS: A recent study showed a high accuracy rate for FNA cytology (FNAC) in combination with immunostaining as a diagnostic method in 26 children with NT. In the current study FNA smears from 18 children were analyzed, either at the time of diagnosis or retrospectively, on available stored smears for cellular DNA content (DNA ploidy) by means of image cytometry (ICM) and 1p deletion and N-myc amplification by interphase fluorescent in situ hybridization (FISH). RESULTS: A total 62 analyses (DNA ploidy, 20 analyses; chromosome 1 or 2 number, 11 analyses; 1p deletion, 16 analyses; and N-myc, 15 analyses) resulted in clear information in 60 cases, whereas 2 tests for N-myc amplification failed. The results were compared with each other and with cytometric DNA analyses on tumor touch imprints (n = 12) and N-myc analyses on material from surgical specimens (Southern blot analysis, n = 12). The results were concordant in all but seven analyses (all with clear informative results) in six children. These discrepancies may be explained as an effect of either chemotherapy or tumor heterogeneity. CONCLUSIONS: FNA is a fast and noninvasive diagnostic technique that yields sufficient material for the molecular characterization of neuroblastic tumors by means of FISH and ICM. Such analyses are of prognostic significance because they predict tumor behavior and response to therapy according to International Neuroblastoma Staging System/International Neuroblastoma Risk Groups criteria. In the majority of cases it also is possible to obtain material for storage and future investigations.

Biopsy, Needle↗

PubMed2003

Beta-catenin mutations in liver tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline in CDF1 mice.

Heterocyclic amines are potent mutagens and carcinogens formed in cooked protein rich foods. In this study, we screened liver tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) in CDF1 mice for beta-catenin and APC mutations and other genetic alterations shown to occur in human hepatocellular carcinomas (HCC), including mutations in the p53 and H-ras genes, c-myc amplification and E-cadherin promoter methylation. SSCP followed by direct DNA sequencing revealed mutations in exon 2 of the beta-catenin gene in 2 of 16 liver tumors (12.5%). Promoter methylation of the E-cadherin gene was detected in one liver tumor induced by MeIQ. There were no mutations in the mutation cluster region of the APC gene, in exons 5-8 of the p53 gene, or in codons 12, 13 and 61 of the H-ras gene, nor c-myc amplification in any of liver tumors induced by MeIQ. These data indicate that except for the occasional disruption of the Wnt pathway through beta-catenin mutations, the genetic pathways involved in the development of HCC differ significantly between human liver cancer and tumors induced in mice by MeIQ, but do not rule out the possibility that heterocyclic amines constitute a carcinogenic risk factor in humans.

Animals↗

PubMed1992

Neuroblastoma. Effect of genetic factors on prognosis and treatment.

BACKGROUND AND METHODS. Genetic analysis of tumor tissue has provided considerable insight into mechanisms of malignant transformation and progression. Neuroblastomas have been studied by cytogenetics, flow cytometry, and molecular genetic techniques, and these studies have identified several specific abnormalities that allow subclassification of these tumors into genetic/clinical subtypes. RESULTS AND DISCUSSION. Four genetic abnormalities have been identified that are characteristic of certain neuroblastomas. These include: (1) loss of heterozygosity (LOH) for the short arm of chromosome 1, including band 1p36; (2) amplification of the N-myc protooncogene; (3) hyperdiploidy, or near triploidy; and (4) defects in expression or function of the nerve growth factor receptor (NGFR). Abnormalities of the NGFR are found in virtually all neuroblastoma cell lines, and some primary tumors. The latter have not been studied extensively. Hyperdiploidy is associated with lower stages of disease and with a favorable outcome in infants. LOH for chromomors. The latter have not been studied extensively. Hyperdiploidy is associated with lower stages of disease and with a favorable outcome in infants. LOH for chromosome 1, band p36, and N-myc amplification are more common in patients older than 1 year of age with advanced stages of disease. The latter two genetic abnormalities may be related, and LOH for 1p36 may precede the development of amplification. When these abnormalities are combined with assessment of DNA content, three distinct genetic subsets of neuroblastomas can be identified. The first is characterized by a hyperdiploid or near-triploid modal karyotype, with few if any cytogenetic rearrangements. These patients generally are younger than 1 year of age with localized disease and a good prognosis. The second has a near-diploid karyotype, with no consistent abnormality identified currently. These patients generally are older with more advanced stages of disease that progress slowly and are often fatal. The third group has a near-diploid or tetraploid karyotype, with deletions or LOH for 1p36, amplification of N-myc, or both. These patients generally are older with advanced stages of disease that rapidly are progressive. Thus, genetic analysis of neuroblastoma cells provides information that has prognostic significance and can direct a more appropriate choice of treatment.

Cell Line↗

PubMed1998

The p16 (CDKN2A) gene is involved in the growth of neuroblastoma cells and its expression is associated with prognosis of neuroblastoma patients.

We previously reported that loss of heterozygosity (LOH) on chromosome 9p21 correlates with poor prognosis of neuroblastoma and the p16 gene is not expressed in approximately two thirds of neuroblastoma cell lines. Here we demonstrated that p16 expression was induced by 5-aza-2-deoxycytidine treatment in cell lines with 5' CpG island methylation but not in cell lines without methylation. Furthermore, the cell cycle of neuroblastoma cell lines significantly delayed with accumulation of cells in G1 phase by transfection of a wild-type p16 expression vector. These results indicate that p16 is inactivated in part by DNA methylation and its expression is involved in the growth of neuroblastoma cells in vitro. To assess the biological and clinical significance of p16 expression in primary tumors, we undertook immunohistochemical analysis in 74 paraffin sections of neuroblastomas. p16 protein was undetectable in 45 of 74 cases (61%) and lack of p16 expression significantly correlated with poor prognosis of patients and advanced stage of the disease. There was no correlation between loss of p16 expression and N-myc amplification in these tumors. These results indicate that inactivation of the p16 gene is involved in the progression of neuroblastoma independently of N-myc amplification.

Azacitidine↗

PubMed1989

Selection of cells with different chromosomal localizations of the amplified c-myc gene during in vivo and in vitro growth of the breast carcinoma cell line SW 613-S.

The c-myc gene is amplified in the human breast carcinoma cell line SW 613-S. At early in vitro passages, the extra copies of the gene were mainly localized in double minute chromosomes (DMs), as shown by in situ hybridization with a biotinylated c-myc probe. However, cells without DMs were also present in which the c-myc genes were found integrated into any of several distinct chromosomes (mainly 7q+, 4 and 4q+, and 1). When this cell line was propagated in vitro, the level of c-myc amplification decreased because cells with DMs and a high amplification level were lost and replaced by cells without DMs and having a low amplification level. On the contrary, when early passage SW 613-S cells were grown in vivo, as subcutaneous tumours in nude mice, cells with numerous DMs and a high level of c-myc amplification were selected for. In one cell line (SW 613-Tu1) established from such a tumour, the DM-containing cells were substituted at late passages for cells with a high number of c-myc copies integrated within an abnormally banded region, at band 17q24 of a 17q+ chromosome. When only cells with integrated genes were present, this cell line was still highly tumorigenic indicating that the localization of the c-myc genes in DMs was not required for these cells to be tumorigenic in nude mice. Furthermore, cells of the secondary tumours induced by SW 613-Tu1 did not contain any DMs showing that in vivo growth did not promote the release of integrated c-myc copies into DMs.

Blotting, Southern↗

PubMed1985

Variation in myc gene amplification and expression in sublines of HL60 cells.

Three sublines of the human promyelocytic leukaemia cell line HL60 have been isolated. Histochemical, karyotypic and immunological analyses have confirmed the identity of the three sublines as HL60. However, the extent to which c-myc homologous DNA sequences are amplified in the genomes of these cells varies from 4- to 30-fold. Moreover, the relative abundance of c-myc-related RNA sequences in uninduced cells of each subline is directly proportional to the gene copy number. It is concluded that, while high levels of the c-myc gene and its transcripts may have had a role in the establishment of HL60 cells, these are not required for maintenance of the HL60 phenotype. However we cannot rule out the possibility that a low level of amplification and enhancement of transcription has a role in maintenance of this phenotype.

Antibodies, Monoclonal↗

PubMed1997

Two transcription factors, E1AF and N-myc, correlate with the invasiveness of neuroblastoma cell lines.

The ets transcription factor E1AF can activate several matrix-degrading metalloproteinase (MMP) genes and is implicated in enhancement of tumor cell invasion. Here we compared the invasive activity of five human neuroblastoma cell lines (TGW, GOTO, SK-N-BE, SK-N-SH and SK-N-AS), which exhibit distinct levels of N-myc amplification, together with the expression of E1AF. Extracellular matrix-degrading proteases and their inhibitor proteins, which play an important role in local invasion, were also analyzed. The activity to invade through reconstituted basement membrane was high in cells (TGW, GOTO, and SK-N-BE) with N-myc amplification, and these cells produced relatively large amounts of E1AF mRNA, correlating with the invasive activities. Of several matrix metalloproteinases (MMPs) and a tissue inhibitor of MMPs (TIMP), only membrane-bound type 1 MMP (MT1-MMP) was specifically detected in N-myc-amplified cells, suggesting a role of MT1-MMP in neuroblastoma cell invasion. MMP-2 (72 kD type IV collagenase), TIMP-1 and TIMP-2 were expressed in all five cell lines. Urokinase-type plasminogen activator was undetectable. These findings indicate that the transcription factors E1AF and N-myc are related to malignant phenotypes of neuroblastoma.

Adenovirus E1A Proteins↗

PubMed1996

Lack of class I HLA expression in neuroblastoma is associated with high N-myc expression and hypomethylation due to loss of the MEMO-1 locus.

Class I HLA expression is low in neuroblastoma tumours and cell lines. We have recently mapped a modifier of methylation for HLA-C (MEMO-1) to chromosomal bands 1p35-36.1, a region deleted in many neuroblastomas. Hypomethylation of HLA-C is strongly correlated with allelic loss of the MEMO-1 locus. Here, we show that loss of MEMO-1 is associated with hypomethylation of both the 5' and 3' regions of class I HLA loci. We next investigated the relationship between methylation and expression of class I HLA in 28 cell lines of neuroectodermal tumours. Cell lines with hypermethylated HLA-C and HLA-A loci have relatively high expression, while most cell lines with hypomethylated loci have no or a reduced expression. It was reported earlier that high expression of c- or N-myc can suppress class I HLA expression. Remarkably, also N-myc amplification in neuroblastomas is associated with allelic loss of 1p35-36. Therefore, we have analysed the relationships between allelic loss of the MEMO-1 locus, class I HLA methylation and expression, and N-myc amplification and expression. This study shows a tight inter-relationship between these phenomena. Our data suggest a model in which hypomethylation of class I HLA due to loss of the MEMO-1 locus and high N-myc expression could collaborate in the down-regulation of class I HLA expression.

Cell Fusion↗

PubMed1991

N-myc oncogene amplification in a pediatric case of glioblastoma multiforme.

A sample of a primary brain tumor of glial cell origin was surgically removed from a 7-year-old girl. The histopathological analysis showed a heterogeneous tumor containing highly cellular areas composed of small, poorly differentiated cells with frequent mitoses suggestive of a glioblastoma multiforme. There were also areas presenting as features of lower-grade astrocytoma. Strong immunohistochemical staining for glial fibrillar acidic protein was demonstrated, while vimentin, neurofilament, and S-100 protein were all positive in just the astrocytic part of the tumor. The DNA extracted from a fresh tumor sample at diagnosis was processed by Southern blot analysis and hybridized with a 2.0 kb N-myc oncogene probe recognizing the first intron and the second exon of the human gene. A 20-fold amplification of the oncogene was found. The possible role of such a molecular alteration is discussed in light of the clinical presentation and histopathological features.

Biomarkers, Tumor↗

PubMed1990

Amplification of the c-myc oncogene during progression of radiation-induced rat skin tumors.

Evaluation of a large panel of radiation-induced rat skin tumors of diverse size and histological type revealed a correlation between c-myc copy number and tumor size. Both the frequency and degree of c-myc gene amplification were increased in large compared to small carcinomas, but none of the sarcomas examined showed c-myc amplification. Serial biopsies of individual tumors exhibited similar trends of increasing c-myc copy number in later biopsies. In one regressing tumor, the c-myc gene copy number paralleled the growth rate of the tumor during growth and regression. The average time required from tumor appearance to significant gene amplification was close to the average period between tumor appearance and the onset of rapid growth. The data suggest that, rather than being a target gene for the direct early effects of ionizing radiation, c-myc functions as a late-stage progression-related oncogene in this model system.

Animals↗

PubMed1997

Comparative genomic hybridization (CGH) analysis of neuroblastomas--an important methodological approach in paediatric tumour pathology.

Comparative genomic hybridization (CGH) was applied to 35 neuroblastomas to obtain a global view of genetic imbalances. Results were validated by means of Southern blot hybridization (detection of N-myc amplification), loss of heterozygosity (LOH) studies (detection of deletion 1p), and interphase cytogenetics [dual labelling fluorescence in situ hybridization (FISH) of centromeric 17 and erbB-2]. CGH allowed sensitive detection of N-myc amplification and chromosome 1p deletion, representing the most established prognostic markers of neuroblastoma. In addition, a high rate of chromosome 17 aberrations (63 per cent) with possible prognostic relevance was observed. Previously unreported high level copy number increases indicating oncogene amplification were mapped to chromosome subbands 2p13-14 and 3q24-26. Other recurrent regional chromosomal aberrations were localized on 11q, 12q, 13q, 14q, and 15q. CGH results were fully consistent with data of Southern blot analysis and LOH study, as well as interphase cytogenetics. These results show that CGH is a sensitive method for the detection of all prognostically relevant genetic alterations in neuroblastomas; that CGH considerably simplifies the detection of these alterations, resulting in a single methodological approach; and that CGH is a powerful tool to elucidate previously unknown genetic changes in neuroblastomas.

Blotting, Southern↗

PubMed1994

Expression and function of TRK-B and BDNF in human neuroblastomas.

There is considerable interest in the role of the TRK family of neuotrophin receptors in regulating growth and differentiation in normal and neoplastic nerve cells. A neuroblastoma is a common pediatric tumor derived from the neural crest, and the majority of favorable neuroblastomas express a high level of TRK-A mRNA. However, little is known about the expression or function of TRK-B in these tumors. TRK-B encodes a tyrosine kinase that binds to brain-derived neuotrophic factor (BDNF), as well as neurotrophin-3 (NT-3) and NT-4/5. We have studied the N-myc-amplified human neuroblastoma cell line, SMS-KCN, which expresses both TRK-B and BDNF. Exogenous BDNF induces tyrosine phosphorylation of TRK-B as well as phosphorylation of phospholipase C-gamma 1, the extracellular signal-regulated kinases 1 and 2, and phosphatidylinositol-3 kinase. BDNF also induces expression of the immediate-early genes c-FOS and NGFI-A but not NGFI-B or NGFI-C. In addition, BDNF appears to promote cell survival and neurite outgrowth. SMS-KCN cells also express TRK-A, which is phosphorylated in response to nerve growth factor. However, the downstream TRK-A signaling is apparently defective. Finally, we determined that in a series of 74 primary neuroblastomas, 36% express TRK-B mRNA, 68% express BDNF mRNA, and 31% express both. Truncated TRK-B appears to be preferentially expressed in more-differentiated tumors (ganglioneuromas and ganglioneuroblastomas), whereas full-length TRK-B is expressed almost exclusively in immature neuroblastomas with N-myc amplification. Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner. The BDNF/TRK-B pathway may be particularly important for growth and differentiation of neuroblastomas with N-myc amplification.

Brain-Derived Neurotrophic Factor↗

PubMed1993

Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma.

BACKGROUND AND METHODS: The nerve growth factor receptor is expressed in some neuroblastomas, in which its primary component is encoded by the TRK protooncogene. To determine the relation of the expression of TRK messenger RNA in neuroblastomas to other clinical and laboratory variables, we studied frozen tumor samples from 77 patients. In addition, we tested two primary neuroblastomas that expressed TRK for responsiveness to nerve growth factor. RESULTS: TRK expression strongly correlated with favorable tumor stage (I, II, and IVS vs. III and IV), younger age (< 1 year vs. > or = 1 year), normal N-myc copy number, and low level of N-myc expression. N-myc amplification (indicated by a high copy number) correlated with advanced tumor stage, older age, an adrenal site of the primary tumor, low level of expression of TRK, and high level of expression of N-myc. Analysis of five-year cumulative-survival rates demonstrated an association of a very favorable outcome with a high level of TRK expression (86 percent vs. 14 percent) and with normal N-myc copy number (84 percent vs. 0 percent). Univariate analysis showed that these two variables were the most powerful predictors of outcome (chi-square = 51.30, P < 0.001; and chi-square = 93.61, P < 0.001, respectively). TRK expression still had significant prognostic value when the analysis was restricted to tumors without N-myc amplification. In primary cultures of neuroblastoma cells expressing TRK, exposure to nerve growth factor induced early gene expression and neurite outgrowth, but deprivation of nerve growth factor led to neuronal cell death. CONCLUSIONS: A high level of expression of the TRK proto-oncogene in a neuroblastoma is strongly predictive of a favorable outcome. A tumor with a functional nerve growth factor receptor may be dependent on the neurotrophin nerve growth factor for survival and may regress in its absence, allowing a new approach to the treatment of certain patients with neuroblastoma.

Age Factors↗

PubMed1988

Amplified allele of the human N-myc oncogene in neuroblastomas.

The N-myc amplification unit was investigated using two restriction fragment length polymorphisms for SphI and PvuII which we previously found to occur in the 2nd intron and in the 3' region of the human N-myc oncogene, respectively. All the three haplotypes which are dominant in the Japanese population were observed in the amplified DNA after analyses of a total of 22 DNA samples of fresh neuroblastomas with N-myc amplification. We conclude that only one of the alleles was amplified and that either allele could be amplified with respect to both the SphI and PvuII polymorphisms.

Alleles↗

PubMed1988

Retrospective study on amplification of N-myc and c-myc genes in pediatric solid tumors and its association with prognosis and tumor differentiation.

DNA was extracted from formalin-fixed and paraffin-embedded tissues of 85 patients with pediatric malignant solid tumors which had been resected at surgery or obtained at autopsy during a 24-year period. The tumors examined included 25 rhabdomyosarcomas, 12 Wilms' tumors, 10 hepatoblastomas and 37 neuroblastoma group tumors. Neuroblastoma group tumors were subclassified into 25 neuroblastomas and 12 ganglioneuroblastomas among which 6 composite ganglioneuroblastomas were included. Sample blocks were selected from both tumors and normal tissues in the majority of cases. We were able to reliably detect N- and c-myc gene amplification in tumor DNA by dot blot-hybridization. The N-myc gene showed approximately from 3- to 500-fold amplification in 19 of 33 cases of stage IV neuroblastoma group tumor. All of these 33 patients had been intensively treated with chemotherapy and/or radiotherapy. The c-myc was amplified 8-fold in 1 case of rhabdomyosarcoma, but neither N-myc nor c-myc was amplified in any cases of Wilms' tumor or hepatoblastoma. We retrospectively examined the association among N-myc gene amplification, prognosis, and histologic subtype in 33 patients with stage IV neuroblastoma group tumors. The survival of the patients with N-myc gene amplification was shorter than that of the patients without amplification of N-myc (p less than 0.05). There was no significant difference in prognosis between the 2 histologic subtypes; neuroblastoma and ganglioneuroblastoma, and the cases of tumors with amplified N-myc showed shorter survivals for each subtype (p less than 0.05). In every case of neuroblastoma group tumor, the copy number of the N-myc gene was the same among primary site and multiple metastatic tumors, even when the lesions showed differences in histologic subtype like neuroblastoma and ganglioneuroblastoma.

Child↗

PubMed1997

Expression of TrkA, TrkB and TrkC in human neuroblastomas.

There is considerable interest in the role of the TRK family of neurotrophin receptors in regulating the survival, growth and differentiation of normal and neoplastic nerve cells. Indeed, there is increasing evidence that TRK genes play an important role in the biology and clinical behavior of neuroblastomas, tumors of the peripheral nervous system. Evidence from several independent studies suggests that high expression of TrkA is an indicator of favorable outcome, and there is an inverse correlation between TrkA expression and N-myc amplification. In addition, some primary neuroblastomas differentiate in vitro in the presence of NGF but die in its absence. We have evidence that coexpression of full-length TrkB and BDNF is associated with N-myc amplification and may represent an autocrine survival pathway. Conversely, truncated TrkB is expressed predominantly in differentiated tumors. Finally, Trk-C is expressed in favorable neuroblastomas, essentially all of which also express TrkA. In summary, the study of neurotrophin receptor expression and function in neuroblastomas may provide important insights into the role that these pathways play in the pathogenesis and clinical behavior of this tumor. Ultimately, these pathways may provide attractive targets for the development of therapy aimed at inducing differentiation or programmed cell death in these tumors.

Brain-Derived Neurotrophic Factor↗

PubMed1992

Molecular basis of clinical heterogeneity in neuroblastoma.

Neuroblastomas are heterogeneous in terms of both their genotype and their clinical behavior. Recent studies suggest that these two features are related, and that the genotype frequently is predictive of response to treatment or the outcome of the patient. The genetic abnormalities that are characteristic of certain neuroblastomas include: (a) loss of heterozygosity (LOH) for the short arm of chromosome 1, including band 1p36; (b) amplification of the N-myc protooncogene; and (c) hyperdiploidy, or near-triploidy, determined either by flow cytometry or by karyotype. Hyperdiploidy is associated with lower stages of the tumor and with a favorable outcome in infants. However, LOH for chromosome 1 (band p36) and N-myc amplification are more common in patients over 1 year of age who have advanced stages of the tumor. Based on analysis of neuroblastomas for these genetic abnormalities, three distinct genetic subsets can be identified. The first is characterized by a hyperdiploid or near-triploid modal karyotype, with few, if any, cytogenetic rearrangements. These patients are generally less than 1 year of age, they have localized tumors, and have a good prognosis. The second genetic subset has a near-diploid karyotype, but with no consistent abnormality identified to date. They are generally older patients with tumors in the more advanced stages that progress slowly and are often fatal. Patients in the third group of genetic abnormalities have a near-diploid or tetraploid karyotype, with deletions or loss of heterozygosity for 1p36, amplification of N-myc, or both. These patients are generally older; they have advanced stage tumors that are rapidly progressive.(ABSTRACT TRUNCATED AT 250 WORDS)

Aneuploidy↗