Peifer, Martin ORCID: 0000-0002-5243-5503, Hertwig, Falk ORCID: 0000-0003-4784-6516, Roels, Frederik, Dreidax, Daniel, Gartlgruber, Moritz, Menon, Roopika, Kraemer, Andrea, Roncaioli, Justin L., Sand, Frederik, Heuckmann, Johannes M., Ikram, Fakhera ORCID: 0000-0001-7796-4746, Schmidt, Rene, Ackermann, Sandra, Engesser, Anne, Kahlert, Yvonne, Vogel, Wenzel, Altmueller, Janine, Nuernberg, Peter, Thierry-Mieg, Jean, Thierry-Mieg, Danielle ORCID: 0000-0001-9568-4211, Mariappan, Aruljothi, Heynck, Stefanie, Mariotti, Erika, Henrich, Kai-Oliver, Gloeckner, Christian, Bosco, Graziella, Leuschner, Ivo, Schweiger, Michal R., Savelyeva, Larissa, Watkins, Simon C., Shao, Chunxuan, Bell, Emma, Hoefer, Thomas, Achter, Viktor, Lang, Ulrich ORCID: 0000-0001-7166-0805, Theissen, Jessica, Volland, Ruth, Saadati, Maral, Eggert, Angelika ORCID: 0000-0003-3476-8184, de Wilde, Bram, Berthold, Frank, Peng, Zhiyu, Zhao, Chen, Shi, Leming, Ortmann, Monika, Buettner, Reinhard, Perner, Sven, Hero, Barbara, Schramm, Alexander, Schulte, Johannes H., Herrmann, Carl ORCID: 0000-0003-4989-4722, O'Sullivan, Roderick J., Westermann, Frank, Thomas, Roman K. and Fischer, Matthias (2015). Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature, 526 (7575). S. 700 - 705. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system(1). 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(2-4). 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(1,2,5). 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Hertwig, FalkUNSPECIFIEDorcid.org/0000-0003-4784-6516UNSPECIFIED
Roels, FrederikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dreidax, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gartlgruber, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menon, RoopikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kraemer, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roncaioli, Justin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sand, FrederikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ikram, FakheraUNSPECIFIEDorcid.org/0000-0001-7796-4746UNSPECIFIED
Schmidt, ReneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ackermann, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engesser, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kahlert, YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogel, WenzelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thierry-Mieg, JeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thierry-Mieg, DanielleUNSPECIFIEDorcid.org/0000-0001-9568-4211UNSPECIFIED
Mariappan, AruljothiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heynck, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mariotti, ErikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henrich, Kai-OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gloeckner, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bosco, GraziellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leuschner, IvoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savelyeva, LarissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Watkins, Simon C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shao, ChunxuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bell, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoefer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Achter, ViktorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, UlrichUNSPECIFIEDorcid.org/0000-0001-7166-0805UNSPECIFIED
Theissen, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volland, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saadati, MaralUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggert, AngelikaUNSPECIFIEDorcid.org/0000-0003-3476-8184UNSPECIFIED
de Wilde, BramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berthold, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peng, ZhiyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhao, ChenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shi, LemingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortmann, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hero, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schramm, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Johannes H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrmann, CarlUNSPECIFIEDorcid.org/0000-0003-4989-4722UNSPECIFIED
O'Sullivan, Roderick J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-389321
DOI: 10.1038/nature14980
Journal or Publication Title: Nature
Volume: 526
Number: 7575
Page Range: S. 700 - 705
Date: 2015
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4687
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TERT PROMOTER MUTATIONS; GENE; LANDSCAPE; ENHANCERS; MELANOMAMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/38932

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