Journal
ONCOGENE
Volume 24, Issue 20, Pages 3377-3384Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208486
Keywords
neuroblastoma; chromosome 17; translocation breakpoint; molecular cloning; interstitial telomere
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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.
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