myc gene amplification and expression in primary human neuroblastoma.
Irene SlavcRichard G. EllenbogenWoo‐Hee JungGordon F. VawterCynthia S. KretschmarHolcombe E. GrierBruce R. Korf
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Although N-myc amplification in neuroblastomas correlates with poor prognosis, not all neuroblastomas which fail to respond to therapy have N-myc amplification. To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-myc, c-myc and L-myc and 26 were studied for transcription of these oncogenes. N-myc amplification was found in 6 of 45 tumors; no tumor had amplification of c-myc or L-myc. Transcription of both N-myc and c-myc occurred in 21 of 26 neuroblastomas. No tumor without N-myc amplification had a level of N-myc expression near that of a tumor or cell line with amplification. One tumor with N-myc amplification was the only specimen with N-myc but not c-myc expression. Five samples had c-myc but not N-myc expression; all had histological features of ganglioneuroma. DNA index did not correlate with myc gene amplification or expression. It is concluded that N-myc and c-myc are commonly expressed in primary untreated neuroblastomas, but in the absence of N-myc amplification, expression of these genes does not appear to correlate with disease progression.Keywords:
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We have investigated the relationship between the expression of bcl-2 and myc family genes in primary human neuroblastoma (NB) tumors and cell lines. Of 20 NB tumors examined, bcl-2 transcripts were expressed at variable levels in 16 tumors of all clinical stages. Of the 2 tumors with N-myc amplification, one expressed bcl-2 at a high level, whereas the other did so at a low level. In contrast, all NB tumors showed the expression of c-myc and/or N-myc transcripts. Similarly, of 9 NB cell lines with N-myc amplification examined, 6 expressed bcl-2 at high levels, whereas the other 3 expressed it at barely detectable levels. The 3 cell lines without N-myc amplification also expressed bcl-2 protein at high levels. All NB cell lines tested expressed either c-myc or N-myc protein. These data suggest that in NB, there is no significant association between bcl-2 expression and advanced tumor stages or N-myc amplification. The data also show that bcl-2 expression does not always coincide with myc expression in NB, suggesting that bcl-2-independent mechanisms may exist in the bcl-2-negative NB tumor cells in order to suppress the cell death promoting action of high myc expression.
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To investigate the molecular genetic abnormalities of N-myc and C-myc, and their clinical pathological implications in pediatric neuroblastic tumors (NTs).Abnormalities of N-myc were detected by interphase fluorescence in situ hybridization (FISH) technique in 246 cases of NTs, including neuroblastoma (NB,188 cases), ganglioneuroblastoma (GNB, 52 cases), ganglioneuroma (GN, 6 cases), and their association with the histological typing of the tumors and prognosis was analyzed. Abnormalities of C-myc were detected by FISH in 133 cases of NTs.Of the 246 cases of NTs, N-myc amplification was only found in 27 cases (11.0%, 27/246) of NB, but not in any cases of GNB or GN (P < 0.05). 89.0% (219/246) N-myc non-amplification were found in NTs, and it included N-myc gain in 175 cases (71.1%, 175/246) and normal N-myc in 44 cases (17.9%, 44/246). Univariate analysis indicated significantly (P = 0.012) poorer outcome in patients with N-myc amplification than N-myc non-amplification. However no significant difference was observed between N-myc gain cases and normal N-myc cases (P = 0.057). C-myc gain was found in 74 of 133 cases (55.6%) of NTs; no C-myc amplification or translocation was detected. Forty percent (6/15) of cases with N-myc amplification and 57.6% (68/118) of cases with N-myc non-amplification were accompanied by C-myc gain. The difference between N-myc amplification and non-amplification with C-myc gain was not significant (P > 0.05). Univariate analysis indicated that the outcome difference was not statistically significant between C-myc gain cases and normal C-myc cases (P = 0.357).The incidence of N-myc amplification only found in NB is low in pediatric NTs in China. Patients with N-myc amplification predict poorer outcome. No amplification or translocation of C-myc is detected in NTs, whereas C-myc gain is relatively common in NTs. There is no obvious association between N-myc amplification and C-myc gain.
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Journal Article N-myc Oncogene RNA Expression in Neuroblastoma Get access Perry D. Nisen, Perry D. Nisen * Division of Hematology-Oncology, and M. A. Rich, Division of Urology, Department of Pediatrics, Schneider Children's Hospital, Long Island Jewish Medical Center, New Hyde Park, and School of Medicine, State Universityof New York at Stony BrookStony Brook, NY *Correspondence to: Perry Nisen, M.D., Division of Hematology-Oncology, Department of Pediatrics, The University of Texas Southwestern Medical School, Dallas, TX 95235-9063. Search for other works by this author on: Oxford Academic PubMed Google Scholar Pamela G.Waber, Pamela G.Waber Division of Hematology-Oncology, and M. A. Rich, Division of Urology, Department of Pediatrics, Schneider Children's Hospital, Long Island Jewish Medical Center, New Hyde Park, and School of Medicine, State Universityof New York at Stony BrookStony Brook, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar Mark A. Rich, Mark A. Rich Department of Pediatrics, Division of Genetics, Mount Sinai School of MedicineNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar Sean Pierce, Sean Pierce Division of Hematology-Oncology, and M. A. Rich, Division of Urology, Department of Pediatrics, Schneider Children's Hospital, Long Island Jewish Medical Center, New Hyde Park, and School of Medicine, State Universityof New York at Stony BrookStony Brook, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar James R. Garvin, Jr., James R. Garvin, Jr. Division of Pediatric Hematology-Oncology, Babies Hospital, Columbia Presbyterian Medical Center, and Department of Pediatrics, College of Physicians and Surgeons, Columbia UniversityNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar Fred Gilbert, Fred Gilbert Department of Pediatrics, Division of Genetics, Mount Sinai School of MedicineNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar Philip Lanzkowsky Philip Lanzkowsky Division of Hematology-Oncology, and M. A. Rich, Division of Urology, Department of Pediatrics, Schneider Children's Hospital, Long Island Jewish Medical Center, New Hyde Park, and School of Medicine, State Universityof New York at Stony BrookStony Brook, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 20, 21 December 1988, Pages 1633–1637, https://doi.org/10.1093/jnci/80.20.1633 Published: 21 December 1988 Article history Received: 15 August 1988 Revision received: 31 October 1988 Accepted: 31 October 1988 Published: 21 December 1988
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Although N-myc amplification in neuroblastomas correlates with poor prognosis, not all neuroblastomas which fail to respond to therapy have N-myc amplification. To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-myc, c-myc and L-myc and 26 were studied for transcription of these oncogenes. N-myc amplification was found in 6 of 45 tumors; no tumor had amplification of c-myc or L-myc. Transcription of both N-myc and c-myc occurred in 21 of 26 neuroblastomas. No tumor without N-myc amplification had a level of N-myc expression near that of a tumor or cell line with amplification. One tumor with N-myc amplification was the only specimen with N-myc but not c-myc expression. Five samples had c-myc but not N-myc expression; all had histological features of ganglioneuroma. DNA index did not correlate with myc gene amplification or expression. It is concluded that N-myc and c-myc are commonly expressed in primary untreated neuroblastomas, but in the absence of N-myc amplification, expression of these genes does not appear to correlate with disease progression.
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Amplification of the N-myc gene in neuroblastoma correlates with advanced stage and poor prognosis. Association of the expression between N-myc and major histocompatibility complex (MHC) class I genes in 33 neuroblastomas obtained from Japanese children was investigated. Amplification of the N-myc gene was observed in two of five cases in Stage III, six of 11 cases in Stage IV, and one of five cases in Stage IV-S. In each case, the expression of N-myc gene was significantly increased. The expression was also increased in cases without amplification of the N-myc gene, the origin being from the suprarenal region. Expression of the MHC class I gene was significantly decreased in five of these nine with a high level of N-myc expression with amplification. These results suggest that the down-modulation of the MHC class I expression may be associated with the high level of expression and amplification of N-myc gene in the advanced stage of neuroblastoma.
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In neuroblastoma lines in which the N- myc gene is present as a single copy, the expression of N- myc as messenger RNA is increased relative to that in nonneuroblastoma cell lines and tumors. The increase of expression in neuroblastomas with amplified N- myc genes is the result of (i) an increase in the absolute amount of expression of each N- myc gene and (ii) an increase in the copy number of the N- myc gene. A second gene—which is amplified in many of the same lines as N- myc —is expressed to about the same degree in most human cell lines and primary tumors regardless of origin (when normalized to gene copy number). Thus, a change in the regulation of N- myc expression in neuroblastomas and certain other tumors results in greatly increased expression of each N- myc gene copy.
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The MRP gene (Cole et al., Science (Washington DC), 258: 1650-1654, 1992) encodes a membrane-bound glycoprotein the expression of which correlates with non-P-glycoprotein-mediated multidrug resistance in a variety of cultured human cell lines. Using an RNA-polymerase chain reaction assay, expression of this gene was examined in the highly chemoresistant pediatric malignancy, neuroblastoma. MRP expression was observed in 5 human neuroblastoma cell lines and in all 25 primary neuroblastoma tumors of stage I through IVS. Tumors with amplification of the N-myc oncogene were found to have significantly higher MRP expression that those with no amplification (P = 0.0016). Expression of the MRP gene in the tumor specimens was highly correlated with expression of the N-myc gene (P = 0.0009), while expression of the MDR1 gene, encoding P-glycoprotein, was not related to expression of either the N-myc or MRP genes. Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. Expression of the MRP gene is thus common in both primary neuroblastoma tumors and cultured cell lines, and correlates with amplification and overexpression of the N-myc oncogene, which is central to the malignant phenotype of this disease.
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Abstract The distal part of 1p is frequently deleted in aggressive neuroblastoma, and the region is believed to harbor one or more tumor suppressor genes relevant to tumor development. To analyze differences among neuroblastoma tumors, an expression profile was established for the genes mapped within a previously described shortest region of overlap of deletions at 1p36.2. The gene expression levels were quantified by TaqMan real‐time (RT)‐PCR for 30 transcripts using 55 primary neuroblastoma tumors. Here we report on a significant decrease in gene expression of the genes RERE, PIK3CD , LZIC, PGD, and PEX14 and an increase of SLC2A5 when comparing tumors of favorable biology to Stage 4 neuroblastomas. When comparing 1p‐deleted tumors of all stages to tumors with an intact 1p, a significant difference at gene‐by‐gene level in TNFRSF9 , RERE , PIK3CD , CLSTN1 , CTNNBIP1, and CASZ1 was detected. A complete loss of expression could not be seen for any single gene analyzed. Several of the genes with diminished expression in unfavorable or 1p‐deleted tumors have functions that could contribute to tumor development. It is also possible that a combination of lowly expressed genes at 1p, rather than one single classical tumor suppressor gene, causes the unfavorable outcome associated with 1p‐deletion in neuroblastoma. © 2006 Wiley‐Liss, Inc.
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