Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

Molenaar, Jan J.; Koster, Jan; Zwijnenburg, Danny; Sluis, Peter van; Valentijn, Linda J.; Ploeg, Ida van der; Hamdi, Mohamed; Nes, Johan van; Westerman, Bart A.; Arkel, Jennemiek van; Ebus, Marli E.; Haneveld, Franciska; Lakeman, Arjan; Schild, Linda; Molenaar, Piet; Stroeken, Peter; Noesel, Max M. van; Øra, Ingrid; Santo, Evan E.; Caron, Huib N.; Westerhout, Ellen M.; Versteeg, Rogier

doi:10.1038/nature10910

Cited by 797 publications

(888 citation statements)

References 36 publications

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“…18,37 To infer chromothripsis with array-based copy number profiling data, various criteria have been applied, the central common part of which is to identify oscillating copy number states on a single chromosome. [38][39][40][41] On the basis of copy number profiling, chromothripsis was present in an estimated 1-3% of human cancers. 18,42 By contrast, 19% (3/16) of cases (and 38% of the 'S' group) in the current series presented copy number profiles suggesting chromothripsis, a phenomenon unprecedented in adenosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin

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Section: Discussionmentioning

confidence: 99%

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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“…A Kaplan-Meier survival analysis using a microarray data set from 88 neuroblastoma patients 25 revealed that high CYLD expression was associated with better overall survival ( Figure 1a) and relapse-free neuroblastoma patient outcomes (Figure 1b). Furthermore, the relative expression level of CYLD was inversely correlated with tumor stage using the International Neuroblastoma Staging System (Figure 1c).…”

Section: Cyld Expression Is Associated With Clinical Outcomes In Neurmentioning

confidence: 99%

Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

2014

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CYLD is a deubiquitinating (DUB) enzyme that has a pivotal role in modulating nuclear factor kappa B (NF-κB) signaling pathways by removing the lysine 63-and linear-linked ubiquitin chain from substrates such as tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. Loss of CYLD activity is associated with tumorigenicity, and levels of CYLD are lost or downregulated in different types of human tumors. In the present study, we found that high CYLD expression was associated with better overall survival and relapse-free neuroblastoma patient outcome, as well as inversely correlated with the stage of neuroblastoma. Retinoic acid-mediated differentiation of neuroblastoma restored CYLD expression and promoted SUMOylation of CYLD. This posttranslational modification inhibited deubiquitinase activity of CYLD against TRAF2 and TRAF6 and facilitated NF-κB signaling. Overexpression of non-SUMOylatable mutant CYLD in neuroblastoma cells reduced retinoic acid-induced NF-κB activation and differentiation of cells, but instead promoted cell death.

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“…Overall, low-risk neuroblastomas mostly have whole chromosomal gains without structural aberrations. High-risk neuroblastomas, for example, mostly stage 4, on the contrary, present with different structural aberrations in the form of gains or losses of large chromosomal segments, referred to as segmental chromosomal aberrations (SCAs), MYCN amplification (MNA), and/or mutations as well as copy-number alterations affecting certain genes or parts thereof (5)(6)(7)(8)(9)(10)(11)(12)(13). Whether genetic markers might help to identify the relapse-seeding clone and to categorize stage 4 patients into different prognostic subgroups is still a matter of debate.…”

Section: Introductionmentioning

confidence: 99%

“…8 Department of Pediatrics and Adolescent Medicine, Paracelsus Medical University, Salzburg, Austria. 9 Department of Pediatrics, Medical University of Vienna, Vienna, Austria.…”

Section: Introductionmentioning

confidence: 99%

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Abbasi

Rifatbegovic

Brunner

et al. 2017

Clinical Cancer Research

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Purpose: Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones.Experimental design: We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients.Results: In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrowderived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and ATRX deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs.Conclusions: Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. Clin Cancer Res; 23(15); 4224-32.Ó2017 AACR.

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Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

Cited by 797 publications

References 36 publications

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

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