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 elusive2,3,4. 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 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.
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All high-throughput data have been deposited at the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/) under accession number EGAS00001001308.
We are indebted to the patients and their parents for making available the tumour specimens analysed in this study. We thank the German Neuroblastoma Biobank for providing samples from patients. The Institutional Review Board approved collection and use of all specimens in this study. We also thank our colleagues N. Hemstedt, H. Düren, E. Hess, J. Kreth, and J. Gopalakrishnan; and our collaboration partners I. Amit and F. Paul at the Weizmann Institute of Science for technical assistance. We further acknowledge the Center for Molecular Medicine Cologne light microscope facility for helping us to obtain high-quality data of FISH analyses, and S. Wolf and the Next Generation Sequencing Unit at the German Cancer Research Center (DKFZ) for sequencing. This work was supported by the German Cancer Aid (grant 110122) to M.F., F.W., J.H.S., A.S., and S.A.; the German Ministry of Science and Education (BMBF) as part of the e:Med initiative (grant 01ZX1303A to M.P., M.F., J.H.S., R.B., U.L., and R.K.T., grant 01ZX1406 to M.P., and grant 01ZX1307D to M.F. and F.W.); the BMBF (grant 0316076A to F.W.); the European Union (grant 259348 to F.W.); the Fördergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V. (to M.F.); the German-Israeli Helmholtz Research School in Cancer Biology (to M.G. and F.W.); the Volkswagenstiftung (Lichtenberg Program) (to M.R.S.); and the Center for Molecular Medicine Cologne.
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Current Opinion in Pediatrics (2019)