Telomerase activation by genomic rearrangements in high-risk neuroblastoma

• Published in: Nature (London) Vol. 526; no. 7575; pp. 700 - 704
• Main Authors: Peifer, Martin, Hertwig, Falk, Roels, Frederik, Dreidax, Daniel, Gartlgruber, Moritz, Menon, Roopika, Krämer, Andrea, Roncaioli, Justin L., Sand, Frederik, Heuckmann, Johannes M., Ikram, Fakhera, Schmidt, Rene, Ackermann, Sandra, Engesser, Anne, Kahlert, Yvonne, Vogel, Wenzel, Altmüller, Janine, Nürnberg, Peter, Thierry-Mieg, Jean, Thierry-Mieg, Danielle, 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, Höfer, Thomas, Achter, Viktor, Lang, Ulrich, Theissen, Jessica, Volland, Ruth, Saadati, Maral, Eggert, Angelika, de Wilde, Bram, Berthold, Frank, Peng, Zhiyu, Zhao, Chen, Shi, Leming, Ortmann, Monika, Büttner, Reinhard, Perner, Sven, Hero, Barbara, Schramm, Alexander, Schulte, Johannes H., Herrmann, Carl, O’Sullivan, Roderick J., Westermann, Frank, Thomas, Roman K., Fischer, Matthias
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.10.2015; Nature Publishing Group
• Subjects: 101/47; 38/32; 45/22; 45/61; 45/77; 45/90; 45/91; 49/15; 49/23; 631/67/2332; 631/67/69; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Chromatin - genetics; Chromatin - metabolism; Chromosomes; Chromosomes, Human, Pair 5 - genetics; Development and progression; DNA Helicases - genetics; DNA Methylation; Enhancer Elements, Genetic - genetics; Enzyme Activation - genetics; Gene Amplification - genetics; Gene Expression Regulation, Neoplastic - genetics; Gene Silencing; Genes; Genetic aspects; Genome, Human - genetics; Genomics; Humanities and Social Sciences; Humans; Infant; Kinases; letter; multidisciplinary; Mutation; N-Myc Proto-Oncogene Protein; Nervous system; Neuroblastoma; Neuroblastoma - classification; Neuroblastoma - enzymology; Neuroblastoma - genetics; Neuroblastoma - pathology; Nuclear Proteins - genetics; Oncogene Proteins - genetics; Physiological aspects; Prognosis; Recombination, Genetic - genetics; Risk; RNA, Messenger - analysis; RNA, Messenger - genetics; Science; Telomerase; Telomerase - genetics; Telomerase - metabolism; Translocation, Genetic - genetics; Tumors; Up-Regulation - genetics; X-linked Nuclear Protein; Germany
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature14980

Activation of telomere maintenance mechanisms—caused by novel somatic rearrangements of TERT , by MYCN amplification, or ATRX mutations—is a hallmark of high-risk neuroblastomas. TERT mutations in high-risk neuroblastomas About half of individuals with neuroblastomas — paediatric tumours of the sympathetic nervous system — are at high risk of poor clinical outcomes. These authors sequence 39 such neuroblastoma tumours, along with 17 low-risk types, and find that about one-quarter of the former have rearrangements near the telomerase reverse transcriptase ( TERT ) gene that are absent in the latter. TERT -rearranged neuroblastoma cell lines had higher levels of enzymatic telomerase activity than those lacking such rearrangements. These findings suggest that further development of inhibitors of the protein telomerase may lead to a novel therapeutic option for the most aggressive subgroup of this disease. 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 , 3 , 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.