HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsMartin 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-Mieg, Aruljothi 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
JournalNature (Nature) Vol. 526 Issue 7575 Pg. 700-4 (Oct 29 2015) ISSN: 1476-4687 [Electronic] England
PMID26466568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Chromatin
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • RNA, Messenger
  • TERT protein, human
  • Telomerase
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein
Topics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic (genetics)
  • Chromatin (genetics, metabolism)
  • Chromosomes, Human, Pair 5 (genetics)
  • DNA Helicases (genetics)
  • DNA Methylation
  • Enhancer Elements, Genetic (genetics)
  • Enzyme Activation (genetics)
  • Gene Amplification (genetics)
  • Gene Expression Regulation, Neoplastic (genetics)
  • Gene Silencing
  • Genome, Human (genetics)
  • Humans
  • Infant
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma (classification, enzymology, genetics, pathology)
  • Nuclear Proteins (genetics)
  • Oncogene Proteins (genetics)
  • Prognosis
  • RNA, Messenger (analysis, genetics)
  • Recombination, Genetic (genetics)
  • Risk
  • Telomerase (genetics, metabolism)
  • Translocation, Genetic (genetics)
  • Up-Regulation (genetics)
  • X-linked Nuclear Protein

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: