Identification of candidate genes involved in neuroblastoma progression by combining genomic and expression microarrays with survival data

Łastowska, M; Viprey, Virginie; Santibanez‐Koref, Mauro; Wappler, Ilka; Peters, Heiko; Cullinane, Catherine; Roberts, Paul; Hall, Andrew G.; Tweddle, Deborah A.; Pearson, Andrew D.J.; Lewis, Ian; Burchill, S A; Jackson, Michael S.

doi:10.1038/sj.onc.1210552

Cited by 88 publications

(73 citation statements)

References 41 publications

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Section: Discussionmentioning

confidence: 99%

“…4,5,14,53 A number of highly coamplified regions that were discontinuous regarding the MYCN locus and located at varying distances from MYCN were described, demonstrating the unique constitution of the MYCN amplicon. 4,5,14,53 Interestingly, only one group of researchers found high-level amplification of two genes (SNTG2 and TPO) situated at 936 kb and 1.4 Mb, respectively, from 2pter, occurring in one of 10 MNA samples. 5 In contrast, array expression studies from two independent groups reported the frequent occurrence of elevated expression levels of the genes SH3YL1, 26 ACP1, 49 and RPS7 26,49 situated at 208 kb, 250 kb, and 3.6 Mb, respectively, from 2pter, thus confirming our data.…”

Section: Discussionmentioning

confidence: 99%

“…The size of the MYCN amplicon can extend anywhere from 350 kb to 8 Mb in length, [3][4][5] demonstrating the great variability of amplicon sizes and the number of coamplified genes in NB. A frequently coamplified gene is DDXI (mapping position 2p24), belonging to a family of genes that encode DEAD (Asp-Glu-Ala-Asp) box proteins, implicated in a number of cellular processes, eg, in posttranscriptional and translational gene regulation.…”

mentioning

confidence: 99%

“…Finally, coamplification of the ALK (anaplastic lymphoma kinase) gene is reported to occur rarely and is observed only in cases with poor outcome. 17 In the last 2 years, array comparative genomic hybridization (CGH) 5,18,19 and expression profiling 20 -24 have increasingly been used to identify new genes involved in NB disease. However, published data are difficult to compare with each other for two main reasons.…”

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confidence: 99%

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Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

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Bozsaky

Watzinger

et al. 2008

The American Journal of Pathology

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MYCN amplification is associated with poor prognosis in neuroblastoma disease. To improve our understanding of the influence of the MYCN amplicon and its corresponding expression, we investigated the 2p expression pattern of MYCN amplified (n ‫؍‬ 13) and nonamplified (n ‫؍‬ 4) cell lines and corresponding primary tumors (n ‫؍‬ 3) using the comparative expressed sequence hybridization technique. All but one MYCN amplified cell line displayed overexpression at 2p. Expression peaks were observed frequently at 2pter and less frequently at 2p24 (MYCN locus), 2p23.3-23.2, and/or 2p23.1. Importantly, cell lines and two corresponding primary tumors displayed expression peaks at similar loci. No significant 2p24 expression level was observed for those cell lines displaying a low amplification rate (n ‫؍‬ 3) by comparative genomic hybridization. Only the cell lines with an enhanced peak at 2p23.2-23.3 displayed coamplification of the ALK gene (2p23.2), reported to be associated with unfavorable prognosis. Finally, two of four cell lines without MYCN amplification, both derived from patients with poor outcome, also showed an expression peak at 2p23.2. These data indicate that, besides MYCN, other genes proximal and distal to MYCN are highly expressed in neuroblastoma. The prognostic significance of expression peaks at 2p23.2-23.3, independent of MYCN and ALK status, remains to be investigated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

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Bozsaky

Watzinger

et al. 2008

The American Journal of Pathology

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“…Segmental chromosomal alterations frequently occur in older children with stage IV tumors and are the strongest predictors of relapse, indicating a role in neuroblastoma pathogenicity (3,4). The most common alterations require DNA double-strand breaks (DSB) resulting in segmental deletions of 1p, 3p, 4p, or 11q and/or gain of 17q, 1q, and 2p regions (5)(6)(7)(8)(9)(10). Affected breakpoints have no DNA sequence similarities and result from unbalanced translocations generated by erroneous repair of DSB (11).…”

Section: Introductionmentioning

confidence: 99%

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Newman

Bashllari

et al. 2015

Molecular Cancer Research

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In neuroblastoma, MYCN genomic amplification and segmental chromosomal alterations including 1p or 11q loss of heterozygocity and/or 17q gain are associated with progression and poor clinical outcome. Segmental alterations are the strongest predictor of relapse and result from unbalanced translocations attributable to erroneous repair of chromosomal breaks. Although sequence analysis of affected genomic regions suggests that these errors arise by nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB), abnormalities in NHEJ have not been implicated in neuroblastoma pathogenesis. On this basis, the hypothesis that an error-prone mechanism of NHEJ is critical for neuroblastoma cell survival was tested. Plasmid-based DSB repair assays demonstrated efficient NHEJ activity in human neuroblastoma cells with repair products that were error-prone relative to nontransformed cells. Neuroblastoma cells derived from tumorigenic neuroblastic phenotypes had differential DNA repair protein expression patterns compared with nontumorigenic cells. Tumorigenic neuroblastoma cells were deficient in DNA ligase IV (Lig4) and Artemis (DCLRE1C), mediators of canonical NHEJ. Conversely, enzymes required for an error-prone alternative NHEJ pathway (alt-NHEJ), DNA Ligase IIIa (Lig3), DNA Ligase I (Lig1), and PARP1 protein were upregulated. Inhibition of Lig3 and Lig1 led to DSB accumulation and cell death, linking alt-NHEJ to cell survival in neuroblastoma. Neuroblastoma cells demonstrated sensitivity to PARP1 inhibition (PARPi) that paralleled PARP1 expression. In a dataset of human neuroblastoma patient tumors, overexpression of genes encoding alt-NHEJ proteins associated with poor survival.Implications: These findings provide an insight into DNA repair fidelity in neuroblastoma and identify components of the alt-NHEJ pathway as promising therapeutic targets. Mol Cancer Res; 13(3); 470-82. Ó2015 AACR.

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Identification of a putative transcriptome signature common to neuroblastoma and neural crest cells

Rabadán

Usieto

Lavarino

et al. 2013

Developmental Neurobiology

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Neuroblastoma, the most common extracranial tumor in children, is caused by genetic lesions in neural crest precursors of the peripheral nervous system. However, since neural crest cells are neither present after birth and nor are they readily accessible for analysis, very little is known about the genetic networks they might share with neuroblastoma cells during their development, despite their common embryonic origin. Here we have developed a novel resource for lineage tracing and for the isolation of neural crest cells in the chick embryo, enabling us to perform a genome-wide expression screen in neural crest progenitors. In this analysis, we efficiently retrieved known neural crest specific genes that validate our screening strategy and we identified new genes that participate in diverse cell activities, yet with a strong representation of genes associated to cell signaling and cell mobility, two hallmarks of migratory cells. We crossed this transcriptome data with that in the neuroblastoma gene server to search for the human orthologues of these genes associated with neuroblastoma. Accordingly, we retrieved 54 genes expressed strongly in both populations, from which we were able to validate a total of 27 genes expressed in the neural crest that are relevant to neuroblastoma formation. We propose that neural crest and neuroblastoma tumor cells share a common genetic signature that might serve to characterize neuroblastoma cancer stem cells, thereby contributing to the identification of specific targets against which new therapeutic strategies can be designed.

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Identification of candidate genes involved in neuroblastoma progression by combining genomic and expression microarrays with survival data

Cited by 88 publications

References 41 publications

Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Identification of a putative transcriptome signature common to neuroblastoma and neural crest cells

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