Telomerase activation by genomic rearrangements in high-risk neuroblastoma
| Autor: | Bram De Wilde, Ulrich Lang, Ruth Volland, Johannes M. Heuckmann, Viktor Achter, Maral Saadati, Danielle Thierry-Mieg, Monika Ortmann, Kai-Oliver Henrich, Zhiyu Peng, Wenzel Vogel, Roman K. Thomas, Justin L. Roncaioli, Angelika Eggert, Ivo Leuschner, Andrea Krämer, Jean Thierry-Mieg, Johannes H. Schulte, Thomas Höfer, Graziella Bosco, Yvonne Kahlert, Peter Nürnberg, Aruljothi Mariappan, Stefanie Heynck, Erika Mariotti, Moritz Gartlgruber, Roderick J. O’Sullivan, Carl Herrmann, Michal R. Schweiger, Christian Gloeckner, Reinhard Büttner, Martin Peifer, Simon C. Watkins, Janine Altmüller, Barbara Hero, Matthias G. Fischer, Frank Berthold, Frederik Sand, Rene Schmidt, Chunxuan Shao, Frederik Roels, Anne Engesser, Fakhera Ikram, Larissa Savelyeva, Falk Hertwig, Sandra Ackermann, Daniel Dreidax, Jessica Theissen, Chen Zhao, Sven Perner, Frank Westermann, Emma Bell, Alexander Schramm, Roopika Menon, Leming Shi |
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| Rok vydání: | 2015 |
| Předmět: |
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X-linked Nuclear Protein Telomerase Medizin Biology N-Myc Proto-Oncogene Protein Translocation Genetic Article Neuroblastoma Cell Line Tumor Gene duplication medicine Humans Gene Silencing RNA Messenger neoplasms ATRX Oncogene Proteins Recombination Genetic Multidisciplinary Genome Human DNA Helicases Gene Amplification Infant Nuclear Proteins DNA Methylation Prognosis medicine.disease Molecular biology Chromatin Up-Regulation Telomere Enzyme Activation Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Enhancer Elements Genetic DNA methylation Chromosomal region Chromosomes Human Pair 5 |
| Zdroj: | Nature. 526:700-704 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system1. 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 elusive2–4. 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 type1,2,5. 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. |
| Databáze: | OpenAIRE |
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