Breakpoint features of genomic rearrangements in neuroblastoma with unbalanced translocations and chromothripsis

PLoS One. 2013 Aug 26;8(8):e72182. doi: 10.1371/journal.pone.0072182. eCollection 2013.


Neuroblastoma is a pediatric cancer of the peripheral nervous system in which structural chromosome aberrations are emblematic of aggressive tumors. In this study, we performed an in-depth analysis of somatic rearrangements in two neuroblastoma cell lines and two primary tumors using paired-end sequencing of mate-pair libraries and RNA-seq. The cell lines presented with typical genetic alterations of neuroblastoma and the two tumors belong to the group of neuroblastoma exhibiting a profile of chromothripsis. Inter and intra-chromosomal rearrangements were identified in the four samples, allowing in particular characterization of unbalanced translocations at high resolution. Using complementary experiments, we further characterized 51 rearrangements at the base pair resolution that revealed 59 DNA junctions. In a subset of cases, complex rearrangements were observed with templated insertion of fragments of nearby sequences. Although we did not identify known particular motifs in the local environment of the breakpoints, we documented frequent microhomologies at the junctions in both chromothripsis and non-chromothripsis associated breakpoints. RNA-seq experiments confirmed expression of several predicted chimeric genes and genes with disrupted exon structure including ALK, NBAS, FHIT, PTPRD and ODZ4. Our study therefore indicates that both non-homologous end joining-mediated repair and replicative processes may account for genomic rearrangements in neuroblastoma. RNA-seq analysis allows the identification of the subset of abnormal transcripts expressed from genomic rearrangements that may be involved in neuroblastoma oncogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases / genetics
  • Anaplastic Lymphoma Kinase
  • Base Sequence
  • Cell Line, Tumor
  • Child, Preschool
  • Chromosome Aberrations*
  • Chromosome Breakpoints*
  • DNA Copy Number Variations
  • Gene Expression Regulation, Neoplastic
  • Gene Rearrangement / genetics*
  • Humans
  • Membrane Glycoproteins / genetics
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Neuroblastoma / genetics*
  • Neuroblastoma / pathology
  • Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics
  • Sequence Analysis, DNA
  • Sequence Homology, Nucleic Acid
  • Transcription, Genetic
  • Translocation, Genetic / genetics*


  • Membrane Glycoproteins
  • NBAS protein, human
  • Neoplasm Proteins
  • fragile histidine triad protein
  • teneurin-4 protein, human
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • PTPRD protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2
  • Acid Anhydride Hydrolases

Grant support

The U830 Inserm laboratory is supported by grants from the Institut National du Cancer, the Ligue Nationale contre le Cancer (Equipe labellisée), the Institut National du Cancer, the ICGEX program, the Association Hubert Gouin, Les Bagouz à Manon, les amis de Claire and Enfants et Santé. GS is supported by the Annenberg Foundation. The U900 Inserm laboratory is supported by the Ligue Nationale Contre le Cancer (Equipe labellisée). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.