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Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

ABSTRACT: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

SUBMITTER: Peifer M

PROVIDER: S-EPMC4881306 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

Peifer Martin M Hertwig Falk F Roels Frederik F Dreidax Daniel D Gartlgruber Moritz M Menon Roopika R Krämer Andrea A Roncaioli Justin L JL Sand Frederik F Heuckmann Johannes M JM Ikram Fakhera F Schmidt Rene R Ackermann Sandra S Engesser Anne A Kahlert Yvonne Y Vogel Wenzel W Altmüller Janine J Nürnberg Peter P Thierry-Mieg Jean J Thierry-Mieg Danielle D Mariappan Aruljothi A Heynck Stefanie S Mariotti Erika E Henrich Kai-Oliver KO Gloeckner Christian C Bosco Graziella G Leuschner Ivo I Schweiger Michal R MR Savelyeva Larissa L Watkins Simon C SC Shao Chunxuan C Bell Emma E Höfer Thomas T Achter Viktor V Lang Ulrich U Theissen Jessica J Volland Ruth R Saadati Maral M Eggert Angelika A de Wilde Bram B Berthold Frank F Peng Zhiyu Z Zhao Chen C Shi Leming L Ortmann Monika M Büttner Reinhard R Perner Sven S Hero Barbara B Schramm Alexander A Schulte Johannes H JH Herrmann Carl C O'Sullivan Roderick J RJ Westermann Frank F Thomas Roman K RK Fischer Matthias M

Nature 20151014 7575

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affectin ...[more]

PMID: 26466568

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Project description:Neuroblastoma (NB) is a heterogeneous pediatric tumor. To better understand the biological pathways involved in the development of high-risk neuroblastoma, we performed parallel global protein and mRNA expression profiling on NB tumors of stage 4 MYCN-amplified (4+) and stage 1 MYCN-not-amplified (1-) using isotope-coded affinity tags (ICAT) and Affymetrix U133plus2 microarray, respectively. A total of 1461 proteins represented by 2 or more peptides were identified from the quantitative ICAT analysis, of which 433 and 130 proteins are up- or down-regulated, respectively, in 4+ tumor compared to the 1- tumor. Pathway analysis of the differentially expressed proteins showed the enrichment of glycolysis, DNA replication and cell cycle processes in the up-regulated proteins and cell adhesion, nervous system development and cell differentiation processes in the down-regulated proteins in 4+ tumor; suggesting a less mature neural and a more invasive phenotype of 4+ tumor. Myc targets and ribosomal proteins are overrepresented in the 4+ tumors as expected; functional gene sets reported to be enriched in neural and embryonic stem cells are significantly enriched in the 4+ tumor, indicating the existence of a stemness signature in MYCN-amplified stage 4 tumor. In addition, protein and mRNA expression are moderately correlated (r = 0.51, p < 0.0001), as approximately half of the up-regulated proteins in 4+ tumor have elevated mRNA level (n = 208), and one-third of down-regulated proteins have lower mRNA expression (n = 47). Further biological network analysis revealed that the differentially expressed proteins closely interact with other proteins of known networks; the important role of MYCN is confirmed and other transcription factors identified in the network may have potential roles in the biology of NB tumor. We used global genomic and proteomic analysis to identify biologically relevant proteins and pathways important to NB progression and development that may provide new insights into the biology of advanced neuroblastoma.

Dataset Information

Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

Publications

Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

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