title: Breakpoint features of genomic rearrangements in neuroblastoma with unbalanced translocations and chromothripsis.
abstract: 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.
authors.affiliation: Inserm, U900, Paris, France ; Institut Curie, Centre de Recherche, Paris, France ; Mines ParisTech, Fontainebleau, France.
authors.forename: Valentina
authors.initials: V
authors.lastname: Boeva
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Jouannet
authors.forename: Romain
authors.initials: R
authors.lastname: Daveau
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.forename: Cécile
authors.initials: C
authors.lastname: Pierre-Eugène
authors.forename: Alex
authors.initials: A
authors.lastname: Cazes
authors.forename: Caroline
authors.initials: C
authors.lastname: Louis-Brennetot
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schleiermacher
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ferrand
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pierron
authors.forename: Alban
authors.initials: A
authors.lastname: Lermine
authors.forename: Thomas
authors.initials: T
authors.lastname: Rio Frio
authors.forename: Virginie
authors.initials: V
authors.lastname: Raynal
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Barillot
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics; D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence; D045744:Cell Line, Tumor; D002675:Child, Preschool; D002869:Chromosome Aberrations; D056905:Chromosome Breakpoints; D056915:DNA Copy Number Variations; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic; D014178:Translocation, Genetic / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000077548:Anaplastic Lymphoma Kinase; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D020794:Receptor Protein-Tyrosine Kinases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D000099170:Bis(5'-adenosyl)triphosphatase; C117339:NBAS protein, human; C576539:TENM4 protein, human; C000626173:ALK protein, human; C090899:PTPRD protein, human