Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma

Janoueix‐Lerosey, Isabelle; Schleiermacher, Gudrun; Michels, Evi; Mosseri, Véronique; Ribeiro, Agnès; Lequin, Delphine; Vermeulen, Joëlle; Couturier, Jérôme; Peuchmaur, Michel; Valent, Alexander; Plantaz, Dominique; Rubie, H; Valteau‐Couanet, Dominique; Thomas, Caroline; Combaret, Valérie; Rousseau, Raphaël F.; Eggert, Angelika; Michon, Jean; Speleman, Frank; Delattre, Olivier

doi:10.1200/jco.2008.16.0630

Cited by 305 publications

(357 citation statements)

References 39 publications

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“…About 76% of tumors of 4S patients have several numerical aberrations confirming previous reports. 21,[31][32][33][34] Although the mechanism responsible for high frequency of numerical CNAs in NBs is unknown, we argue that it may be due to a failure of chromosome segregation during mitosis process. 35 It is noteworthy that three of five patients having disease progression showed 11q loss and 17q gain, and we speculate that these mutations drive the deregulation of tumor suppressor genes located at 11q and/or oncogenes located at 17q regions and responsible for NB aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

Age‐dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma

Coco

Theißen

Scaruffi

et al. 2012

Intl Journal of Cancer

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About 50% of children with neuroblastoma (NB) show a metastatic disease and have a poor prognosis. However, disease progression is greatly variable and depends on patients' age and MYCN oncogene amplification. To investigate the role of patients' age in tumor aggressiveness, we performed array-CGH and gene expression profiles of three groups (G) of metastatic NBs: G1, stage 4S patients and MYCN single copy (MYCN-) tumors; G2, stage 4 patients, ≤18 months of age, MYCN- tumors and favorable outcome and G3, Stage 4 patients, a19 months with unfavorable outcome. G1 was characterized by numerical aberrations prevalently; on the contrary, all G3 tumors had structural rearrangements, whereas G2 showed an intermediate pattern. The average of numerical alterations decreased significantly from G1 to G2 to G3 (p < 0.01). Contrarily, the number of structural aberrations increased from G1 to G2 to G3 (p< 2.35 E-05). Noteworthy, G3/MYCN- NBs were characterized by several complex intrachromosome rearrangements. Expression analysis of the three groups showed significant differences in genes of Rho and Ras signaling pathways, development and adhesion, cell cycle regulation and telomerase activity. Accumulation of structural alterations increased with patients' age and was associated with a more aggressive disease. Abnormal expression of genes involved in cell cycle and telomerase in G3 may be responsible for the genomic instability in this cohort of patients. The higher DNA instability observed in G3/MYCN- NBs than in MYCN-amplified G3 may also explain why patients a19 months have a poor outcome independently by MYCN status. Copyright © 2012 UICC

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Section: Discussionmentioning

confidence: 99%

Age‐dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma

Coco

Theißen

Scaruffi

et al. 2012

Intl Journal of Cancer

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“…Amplification of MYCN (MNA) is associated with rapid tumor progression and advanced stage disease (1, 2). 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).…”

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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“…Next-generation sequencing-based genomic profiling identified the most frequent alterations including MYCN (26.5%), ALK (17.8%), ATRX (6.5%), CDKN2A (4.8%) and RPTOR (4.8%) in 230 neuroblastoma patient samples [7]. Both ALK and MYCN genes are located in chromosome 2p, a chromosomal alteration identified as a statistically significant prognostic factor [8]. It has been shown that ALK and MYCN drive tumor malignancy cooperatively.…”

Section: Introductionmentioning

confidence: 99%