Telomerase activation by genomic rearrangements in high-risk neuroblastoma

Martin Peifer*, Falk Hertwig, Frederik Roels, Daniel Dreidax, Moritz Gartlgruber, Roopika Menon, Andrea Krämer, Justin L. Roncaioli, Frederik Sand, Johannes M. Heuckmann, Fakhera Ikram, Rene Schmidt, Sandra Ackermann, Anne Engesser, Yvonne Kahlert, Wenzel Vogel, Janine Altmüller, Peter Nürnberg, Jean Thierry-Mieg, Danielle Thierry-MiegAruljothi Mariappan, Stefanie Heynck, Erika Mariotti, Kai Oliver Henrich, Christian Gloeckner, Graziella Bosco, Ivo Leuschner, Michal R. Schweiger, Larissa Savelyeva, Simon C. Watkins, Chunxuan Shao, Emma Bell, Thomas Höfer, Viktor Achter, Ulrich Lang, Jessica Theissen, Ruth Volland, Maral Saadati, Angelika Eggert, Bram De Wilde, Frank Berthold, Zhiyu Peng, Chen Zhao, Leming Shi, Monika Ortmann, Reinhard Büttner, Sven Perner, Barbara Hero, Alexander Schramm, Johannes H. Schulte, Carl Herrmann, Roderick J. O'Sullivan, Frank Westermann, Roman K. Thomas, Matthias Fischer

*Korrespondierende/r Autor/-in für diese Arbeit
250 Zitate (Scopus)

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.

OriginalspracheEnglisch
ZeitschriftNature
Jahrgang526
Ausgabenummer7575
Seiten (von - bis)700-704
Seitenumfang5
ISSN0028-0836
DOIs
PublikationsstatusVeröffentlicht - 29.10.2015

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