title: Stepwise occurrence of a complex unbalanced translocation in neuroblastoma leading to insertion of a telomere sequence and late chromosome 17q gain.
abstract: In neuroblastoma, the most frequent genetic alterations are unbalanced translocations involving chromosome 17. To gain insights into these rearrangements, we have characterized a previously identified der(1)t(1;17) of the CLB-Bar cell line. The 17q breakpoint was mapped by FISH. Subsequently, a rearranged fragment was identified by Southern analysis, cloned in a lambda vector and sequenced. The chromosome rearrangement is more complex than expected due to the presence of an interstitial 4p telomeric sequence between chromosome 1p and 17q. Three different genes, which may play a role in neuroblastoma development, are disrupted by the translocation breakpoints. Indeed, the 3'UTR of the PIP5K2B gene on chromosome 17q is directly fused to the (TTAGGG)n repeat of the chromosome 4p telomere, and the (1;4) fusion disrupts the MACF1 (microtubule-actin crosslinking factor 1) and POLN genes, respectively. Interestingly, the (1;4) fusion was present at diagnosis and at relapse, whereas the (4;17) fusion was detected at relapse only, leading to a secondary 17q gain confirmed by array CGH therefore indicating that 17q gain may not be a primary event in neuroblastoma. Finally, screening of a panel of neuroblastoma cell lines identified interstitial telomeric sequences in three other cases, suggesting that this may be a recurrent mechanism leading to unbalanced translocations in neuroblastoma.
authors.affiliation: INSERM Unité 509, Laboratoire de Pathologie Moléculaire des Cancers, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schleiermacher
authors.forename: Franck
authors.initials: F
authors.lastname: Bourdeaut
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.forename: Gaelle
authors.initials: G
authors.lastname: Picrron
authors.forename: Virginie
authors.initials: V
authors.lastname: Raynal
authors.forename: Alain
authors.initials: A
authors.lastname: Aurias
authors.forename: Agnes
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
mesh_terms: D001483:Base Sequence; D015139:Blotting, Southern; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D002886:Chromosomes, Human, Pair 17; D002894:Chromosomes, Human, Pair 4; D003001:Cloning, Molecular; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D016615:Telomere / Q000648:ultrastructure*; D014178:Translocation, Genetic