Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Neuroblastoma has been associated genetically with amplification of the MYCN gene and with alteration of the short arm of chromosome 1 (1p). In pursuit of determining the spectrum of genetic loci damaged recurrently in neuroblastoma cells we have recently encountered two additional types of genomic abnormalities: i.) duplication of the MYCN gene on chromosome 2p24; and ii.) amplification of the gene MDM2. These alterations extend the spectrum of genetic lesions in neuroblastoma cells, although their incidence in primary tumor tissues has not been determined as yet.
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PMID:New genetic loci in neuroblastoma. 929 45

Amplification of MYCN portends rapid tumor progression and poor prognosis in neuroblastoma. MYCN copy number has been described as homogeneous within a tumor and congruent in primary tumor and metastasis. We report a child with stage III favorable histology stroma-rich neuroblastoma (ganglioneuroblastoma) and a poor outcome with an apparent change in MYCN gene amplification by Southern blot. Initial biopsy revealed a ganglioneuroblastoma with predominance of differentiating cells designated as neuroblastoma, stroma-rich, intermixed (Shimada). Southern blot failed to demonstrate MYCN gene amplification. After front-line chemotherapy failed, a total resection was performed. In this specimen, Southern blot demonstrated MYCN amplification (15-20 copies) in the undifferentiated component and no amplification in the differentiated. Fluorescence in situ hybridization (FISH) analysis performed retrospectively on both tumor biopsies demonstrated MYCN amplification in the undifferentiated sections of both tumor specimens but not in the differentiated ones. This is the first well-documented case report of heterogeneous MYCN amplification in a child with neuroblastoma. Because key therapeutic decisions are based on the presence of MYCN amplification, physicians diagnosing and treating children with neuroblastoma need to be aware of the possibility that MYCN amplification may be heterogeneous within a tumor and may be missed using techniques based on pooled DNA such as Southern blotting. FISH may be a preferable method for determining MYCN amplification.
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PMID:Heterogeneity of MYCN amplification in a child with stroma-rich neuroblastoma (ganglioneuroblastoma). 935 27

Neuroblastoma demonstrates various clinical behaviors, ranging from spontaneous regression to rapid progression regardless of the therapy used. To study the possibility that progression occurs in neuroblastoma through the accumulation of genetic aberrations, we analyzed the clonal constitution of the primary tumor and metastatic tumor samples from a stage-4 patient. Using cytofluorometry and FISH analyses, intratumor clonal heterogeneity was revealed. In the initial primary tumor sample, the nuclear DNA content indicated the coexistence of diploid and aneuploid clones, and the copy number of chromosome 1 varied from two to six. The chromosome 1 aneusomy population was composed of MYCN-amplified and 1p-deleted clones, whereas, in the chromosome 1 disomy population, coexistence of MYCN-amplified and non-amplified clones as well as 1p-deleted and 1p-intact clones was revealed. In the primary tumor after chemotherapy, the DNA-diploid component had become predominant, although the coexistence of MYCN-amplified and non-amplified clones could still be demonstrated in poorly- and well-differentiated tumor regions, respectively. This contrasted with the findings in the metastatic tumors, in which either diploid or aneuploid clone with MYCN amplification and 1p deletion dominated completely in each metastatic site. The findings suggest that the aneuploid clones had evolved from a diploid clone with MYCN amplification and a 1p deletion which, in turn, may have evolved from a diploid clone with neither MYCN nor 1p abnormality. This illustrates how various stages of multiple-step tumorigenesis may provide clues to a better understanding of the clinical heterogeneity of neuroblastoma.
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PMID:Human neuroblastoma demonstrating clonal evolution in vivo. 959 33

In order to clarify the biologic characteristics of serous papillary adenocarcinoma of the human ovary, we tried to establish a continuous cell line using four primary tumor specimens derived from four patients with such tumors. We also evaluated c-myc, MYCN and c-erbB2 gene amplification in the cultured cells, and the xenografts, as well as in these four primary tissue specimens by a Southern blot analysis. One continuous cell line, named as FU-OV-1, was established in a serum-free culture system and this line propagated continuously for 96 serial passages over a 2-year-period in vitro. FU-OV-1 reproduced and still maintained the characteristics of the original tumor. C-myc gene amplification was found in the FU-OV-1 cells, and the xenografts, as well as in only the primary tumor of FU-OV-1 out of the four primary serous papillary adenocarcinomas. However, neither MYCN amplification nor c-erbB2 amplification was observed in any tumor specimens including FU-OV-1 cells. In conclusion, FU-OV-1 is thus considered to be a useful system for studying the biological behavior of serous papillary adenocarcinoma in the human ovary. The results of this study suggest that c-myc gene amplification might thus be associated with the progression of this tumor both in vitro and in vivo.
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PMID:Establishment and characterization of a serous papillary adenocarcinoma cell line of the human ovary in a serum-free culture. 1033 61

Amplification of the MYCN gene is significantly associated with an unfavorable prognosis and rapid progression in human neuroblastoma tumors. One potential mechanism by which MYCN may cause these effects is by deregulating cell proliferation. Tissue culture experiments support a model in which MYC genes stimulate cell cycle progression by antagonizing the function of the cell cycle inhibitor p27(kip1). In culture, activation of MYC induces both sequestration of p27(kip1) by cyclin D complexes and its subsequent proteolytic degradation. We have tested whether this model applies to human neuroblastoma in a retrospective study of 100 primary tumor biopsy samples from neuroblastoma patients with a documented follow-up. Consistent with this hypothesis, MYCN-amplified tumors express high levels of both cyclin A and proliferating cell nuclear antigen, 2 marker proteins of cell proliferation. Further, expression levels of p27(kip1) are of prognostic significance in human neuroblastoma patients. Similar to tissue culture systems, p27(kip1) is sequestered by cyclin D complexes in a subset of human neuroblastoma samples. Surprisingly, however, expression levels of p27(kip1) are prognostic independent of MYCN amplification, and tumors that have an amplified MYCN gene do not express elevated levels of D-type cyclins or contain significantly lower levels of p27(kip1). Our data do not support a model in which regulation of p27(kip1) function is an important mechanism by which amplified MYCN deregulates cell proliferation in neuroblastoma.
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PMID:Expression of P27(KIP1) is prognostic and independent of MYCN amplification in human neuroblastoma. 1130 51

The MYCN gene is often amplified but rarely rearranged in neuroblastoma. We report, for the first time, a rearrangement within the MYCN coding region in a metastatic neuroblastoma in a 3-year-old boy with MYCN amplification in his primary tumor. The rearrangement occurred 46 nucleotides downstream from the ATG codon in exon 2 of MYCN. The amplification level of the rearranged copies of the MYCN gene was lower than that of the unrearranged copies of MYCN. These results indicate that the rearrangement occurred after initial MYCN gene amplification. Monochromosomal somatic cell hybrid mapping of the novel region fused to exon 2 of MYCN localized it to chromosome 2, suggesting that this rearrangement resulted from an interstitial deletion, presumably within the MYCN amplicon itself.
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PMID:Rearrangement in the coding region of the MYCN gene in a subset of amplicons in a case of neuroblastoma with MYCN amplification. 1138 18

The p73 gene is a p53 homologue which induces apoptosis and inhibits cell proliferation. Although p73 maps at 1p36.3 and is frequently deleted in neuroblastoma (NB), it does not act as a classic oncosuppressor gene. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). This suggests that p73 may be part of a complex tumor-control mechanism. To determine the role of DeltaNp73 in NB we analyzed the pattern of expression of this gene in vivo and evaluated the prognostic significance of its expression. Our results indicate that DeltaNp73 expression is associated with reduced apoptosis in a NB tumor tissue. Expression of this variant in NB patients significantly correlates with age at diagnosis and VMA urinary excretion. Moreover it is strongly associated with reduced survival (HR=7.93; P<0.001) and progression-free survival (HR=5.3; P<0.001) and its role in predicting a poorer outcome is independent from age, primary tumor site, stage and MYCN amplification (OS: HR=5.24, P=0.012; PFS: HR=4.36, P=0.005). In conclusion our data seem to indicate that DeltaNp73 is a crucial gene in neuroblastoma pathogenesis.
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PMID:Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. 1185 3

Stage 4S neuroblastoma is a disease associated with spontaneous regression and good survival. We present a patient whose evolution has shown the variety and complexity of this disease in infants. Biologic factors, such as ploidy, MYCN copy number, loss of 1p36, and other chromosomal gains and losses were determined. A complex pattern of genetic abnormalities, such as near-diploidy, MYCN gain (2-4 copies per haploid genome) and imbalance/deletion of 1p36 was seen in the diagnostic sample. An extensive disseminated disease after a latent period of 26 months was associated with a special genetic evolution, such a tetraploidy, MYCN amplification (2:100-500 copies), 1p36 deletion, and gain of 17q. Our results provide evidence that either the primary tumor was heterogeneous in terms of gene amplification or that amplification was acquired later on as a transition from MYCN gain. We suggest that near-di-/tetraploid 4S tumors with MYCN gain and/or deletion 1p could be progressing 4S tumors.
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PMID:MYCN gain and MYCN amplification in a stage 4S neuroblastoma. 1264 55

Despite intensive high-dose chemotherapy and autologous hematopoietic stem cell transplantation, disseminated neuroblastoma (NB) frequently proves to be chemosensitive but not chemocurable, and more often so in NB-presenting MYCN amplification. To assess the direct relationship between the MYCN oncogene and chemoresistance acquisition during NB metastatic dissemination, we have studied MYCN and MDR1 genes using the human IGR-N-91 ectopic xenograft metastatic model. This characterized experimental in vitro model includes human neuroblasts derived from a subcutaneous primary tumor xenograft, disseminated blood cells, myocardium, and bone marrow (BM) metastatic cells. All IGR-N-91-derived neuroblasts harbor a consistent MYCN genomic content but, unlike primary tumor xenograft, BM, and myocardium, human neuroblasts elicit a concomitant increase in MYCN and MDR1 transcripts levels, consistent with chemoresistance phenotype and active P-gp. In contrast, no variation of MRP1 transcript level was associated with the metastatic process in this model. Using an MDR1 promoter-CAT construct, we have shown that the MycN protein activates MDR1 transcription both in exogenous transient MYCN-transfected SK-N-SH cells and in endogenous BM metastatic neuroblasts with an increase in the MYCN transcript level. Band-shift experiments indicate that IGR-N-91 cells enriched with the MycN transcription factor do bind to two E-box motifs localized within the MDR1 promoter. Overall, our data indicate that MYCN overexpression increment contributes to the acquired drug resistance that occurs throughout the NB metastatic process.
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PMID:MYCN enhances P-gp/MDR1 gene expression in the human metastatic neuroblastoma IGR-N-91 model. 1281 37


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