Additional copies of a 25 Mb chromosomal region originating from 17q23.1‐17qter are present in 90% of high‐grade neuroblastomas

Meddeb, Mounira; Danglot, Gisèle; Chudoba, Iise; Vénuat, Anne‐Marie; Bénard, Jean; Avet‐Loiseau, Hervé; Vasseur, Béatrice; Paslier, Denis Le; Terrier‐Lacombe, Marie‐Jose; Hartmann, Olivier; Bernheim, Alain

doi:10.1002/(sici)1098-2264(199611)17:3<156::aid-gcc3>3.3.co;2-w

Cited by 8 publications

(12 citation statements)

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“…We suggest that 1q32-q43 gain might be an early event in the development of neuroblastoma. These two distinct regions of gain at 1q have not been reported in previous CGH studies of neuroblastoma (Meddeb et al, 1996;Brinkschmidt et al, 1997;Lastowska et al, 1997a;Plantaz et al, 1997). Some of these investigators have made the threshold of gain and loss less severe, therefore two peaks of gain on 1q might be missed and interpreted as entire 1q gain.…”

Section: Discussionmentioning

confidence: 54%

“…DNA fragment of cosmid CYS1-40 digested by BamH1 was used as a probe. and with a poor prognosis (Meddeb et al, 1996;Brinkschmidt et al, 1997;Lastowska et al, 1997c;Plantaz et al, 1997). In the present study, the frequency of 17q21-q25 gain was significantly higher in stage 4 than in stages 1-3 and 4S; however, we found that all stage 4 neuroblastomas, including PD, UT, and CR cases, showed 17q21-q25 gain.…”

Section: Discussionmentioning

confidence: 99%

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1q23 gain is associated with progressive neuroblastoma resistant to aggressive treatment

Hirai

Yoshida

Kashiwagi

et al. 1999

Genes Chromosomes & Cancer

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Neuroblastoma is one of the most common malignant tumors of childhood and is characterized by regressive and progressive disease. Genetic factors that define progression of neuroblastomas are still unknown. We performed comparative genomic hybridization (CGH) on 27 neuroblastomas and dual‐color fluorescence in situ hybridization (FISH) to identify genetic aberrations associated with progressive neuroblastoma showing resistance to aggressive treatment. 17q21–q25 gains and MYCN amplification were associated with stage 4 neuroblastomas; however, these genetic aberrations had no significant relation to the progression of stage 4 neuroblastomas. A novel chromosomal gain at 1q21–q25 was found in 8 of 16 cases (50%) of stage 4 neuroblastoma. Gain of 1q21–q25 was observed in all of the progressive cases (8/8), which showed resistance to chemotherapy, including 5 fatal neuroblastomas in stage 4, whereas 1q21–q25 gain was not found in any of the 8 remission cases in stage 4. Survival analysis also showed that 1q21–q25 gain was associated with a poor outcome. High xenotransplantability in nude mice was observed for the tumors with 1q21–q25 gain (4/5; 80%). These data show that 1q21–q25 gain is strongly associated with progression of stage 4 neuroblastoma. Furthermore, by dual‐color FISH analysis using cosmid clones, the 1q21–q25 gain was narrowed to increase in DNA copy number on 1q23 in the fatal type of stage 4 neuroblastoma showing this gain. These results suggest that DNA amplification at 1q23 may play a role in the development of progressive neuroblastoma in an advanced stage. Genes Chromosomes Cancer 25:261–269, 1999. © 1999 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

1q23 gain is associated with progressive neuroblastoma resistant to aggressive treatment

Hirai

Yoshida

Kashiwagi

et al. 1999

Genes Chromosomes & Cancer

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“…Survivin is overexpressed in NB and its gene amplification is highly associated with poor prognosis. [5][6][7][9][10][11][12][13] Survivin-specific FIGURE 4 -Induction of target cell lysis, cytokine production and tumor infiltration by CD8 1 T cells. Mice (n 5 6-8) were immunized according to the indicated vaccination protocol (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…3 The survivin gene is mapped to human chromosome 17q25, 4 within the prognostic unfavorable 17 q gain region seen in 90% of advanced stage NB cases. [5][6][7] Increased survivin expression in NB patients was associated with age, stage, unfavorable histology, MYCN amplification and showed to be predictive of recurrent disease and death. [8][9][10][11][12] In addition to the NB-associated survivin overexpression, 9 survivin-specific cytotoxic T cells (CTLs) were detected in NB patients.…”

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confidence: 99%

Survivin minigene DNA vaccination is effective against neuroblastoma

Fest

Huebener

Bleeke

et al. 2009

Intl Journal of Cancer

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The inhibitor of apoptosis protein survivin is highly expressed in neuroblastoma (NB) and survivin-specific T cells were identified in Stage 4 patients. Therefore, we generated a novel survivin minigene DNA vaccine (pUS-high) encoding exclusively for survivinderived peptides with superior MHC class I (H2-K k ) binding affinities and tested its efficacy to suppress tumor growth and metastases in a syngeneic NB mouse model. Vaccination was performed by oral gavage of attenuated Salmonella typhimurium SL7207 carrying pUS-high. Mice receiving the pUS-high in the prophylactic setting presented a 48-52% reduction in s.c. tumor volume, weight and liver metastasis level in contrast to empty vector controls. This response was as effective as a survivin full-length vaccine and was associated with an increased target cell lysis, increased presence of CD8 1 T-cells at the primary tumor site and enhanced production of proinflammatory cytokines by systemic CD8 1 T cells. Furthermore, depletion of CD8 1 but not CD4 1 T-cells completely abrogated the pUS-high mediated primary tumor growth suppression, demonstrating a CD8 1 T-cell mediated effect. Therapeutic vaccination with pUS-high led to complete NB eradication in over 50% of immunized mice and surviving mice showed an over 80% reduction in primary tumor growth upon rechallenge in contrast to controls. In summary, survivin-based DNA vaccination is effective against NB and the rational minigene design provides a promising approach to circumvent potentially hazardous effects of using full length antiapoptotic genes as DNA vaccines. ' UICCKey words: surviving; neuroblastoma; DNA vaccine; Salmonella typhimurium Development of an effective treatment against neuroblastoma (NB), the most common solid extracranial tumor during childhood, is one of the major objectives in pediatric oncology. The inhibitor of apoptosis protein survivin emerges as a suitable target for the establishment of an antineuroblastoma immunotherapy. Survivin is required to maintain cancer cell viability 1,2 and its blockade by antisense oligonucleotides, siRNAs, hammerhead ribozymes or small molecule antagonists lead to an increased tumor cell death rate. 3 The survivin gene is mapped to human chromosome 17q25, 4 within the prognostic unfavorable 17 q gain region seen in 90% of advanced stage NB cases. [5][6][7] Increased survivin expression in NB patients was associated with age, stage, unfavorable histology, MYCN amplification and showed to be predictive of recurrent disease and death. [8][9][10][11][12] In addition to the NB-associated survivin overexpression, 9 survivin-specific cytotoxic T cells (CTLs) were detected in NB patients. 13,14 Accordingly, the first step in targeting survivin for antineuroblastoma immunotherapy has been introduced by Coughlin and colleagues. 15 They primed T cells with CD40-activated B cells (CD40-B) transfected with NB-derived mRNA resulting in a T cell response that lysed HLA-matched NB cells, but not autologous benign cells in vitro. Some of the CTLs were survivinspecific ...

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“…These observations suggest that molecular or genetic factors at diagnosis may discriminate patients with MNA who rapidly progress, from those who will be longterm survivors. Many other molecular and pathologic factors have been identified that are associated with unfavorable outcome in NB, including segmental chromosomal aberrations such as 17q gain (Bown et al, 1999;Meddeb et al, 1996), 1p loss (Attiyeh et al, 2005;Caron et al, 1996), and 11q loss (Schleiermacher et al, , 2012Guo et al, 1999;Caron et al, 1996), diploid/tetraploid status (Ladenstein et al, 2001), and specific genetic alterations of ALK (Bresler et al, 2014) and TERT (Peifer et al, 2015). However, these genomic features and other well-established clinical prognostic variables are highly correlated with MNA status (Thompson et al, 2016) and thus cannot be used to effectively predict outcome and potentially tailor therapy within this unfavorable prognosis subset of MNA patients.…”

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confidence: 99%

Transcript signatures that predict outcome and identify targetable pathways in MYCN‐amplified neuroblastoma

Hallett¹,

Seong²,

Kaplan³

et al. 2016

Molecular Oncology

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Background: In the pediatric cancer neuroblastoma (NB), patients are stratified into low, intermediate or high-risk subsets based in part on MYCN amplification status. While MYCN amplification in general predicts unfavorable outcome, no clinical or genomic factors have been identified that predict outcome within these cohorts of high-risk patients. In particular, it is currently not possible at diagnosis to determine which high-risk neuroblastoma patients will ultimately fail upfront therapy. Experimental design: We analyzed the prognostic potential of most published gene expression signatures for NB and developed a new prognostic signature to predict outcome for patients with MYCN amplification. Network and pathway analyses identified candidate therapeutic targets for this MYCN-amplified patient subset with poor outcome. Results: Most signatures have a high capacity to predict outcome of unselected NB patients.However, the majority of published signatures, as well as most randomly generated signatures, are highly confounded by MYCN amplification, and fail to predict outcome in subpopulations of high-risk patients with MYCN-amplified NB. We identify a MYCN module signature that predicts patient outcome for those with MYCN-amplified tumors, that also predicts potential tractable therapeutic signaling pathways and targets including the DNA repair enzyme Poly [ADP-ribose] polymerase 1 (PARP1). Conclusion: Many prognostic signatures for NB are confounded by MYCN amplification and fail to predict outcome for the subset of high-risk patients with MYCN amplification. We report a MYCN module signature that is associated with distinct patient outcomes, and predicts candidate therapeutic targets in DNA repair pathways, including PARP1 in MYCN-

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Additional copies of a 25 Mb chromosomal region originating from 17q23.1‐17qter are present in 90% of high‐grade neuroblastomas

Cited by 8 publications

References 0 publications

1q23 gain is associated with progressive neuroblastoma resistant to aggressive treatment

1q23 gain is associated with progressive neuroblastoma resistant to aggressive treatment

Survivin minigene DNA vaccination is effective against neuroblastoma

Transcript signatures that predict outcome and identify targetable pathways in MYCN‐amplified neuroblastoma

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