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Nature. 2015 Oct 29;526(7575):700-4. doi: 10.1038/nature14980. Epub 2015 Oct 14.

Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

Author information

1
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
2
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
3
Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, 50937 Cologne, Germany.
4
Division Neuroblastoma Genomics (B087), German Cancer Research Center, 69120 Heidelberg, Germany.
5
Department of Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany.
6
NEO New Oncology AG, 51105 Cologne, Germany.
7
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute (UPCI), Hillman Cancer Center, Pittsburgh, Pennsylvania 15213, USA.
8
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
9
Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany.
10
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
11
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
12
Department of Pathology, University of Kiel, 24118 Kiel, Germany.
13
Functional Epigenomics, University of Cologne, 50931 Cologne, Germany.
14
Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
15
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
16
Computing Center, University of Cologne, 50931 Cologne, Germany.
17
Department of Informatics, University of Cologne, 50931 Cologne, Germany.
18
Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
19
Department of Pediatric Oncology and Hematology, Charité University Medical Center Berlin, 10117 Berlin, Germany.
20
Center for Medical Genetics, Ghent University, 9000 Ghent, Belgium.
21
BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083 China.
22
Center for Pharmacogenomics and Fudan-Zhangjiang Center for Clinical Genomics, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 201203, China.
23
Department of Pathology, University of Cologne, 50937 Cologne, Germany.
24
Department of Pediatric Oncology and Hematology, University Children's Hospital, 45147 Essen, Germany.
25
German Cancer Consortium (DKTK), 10117 Berlin, Germany.
26
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
27
Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany.
28
Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany.
29
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
30
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.

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.

PMID:
26466568
PMCID:
PMC4881306
DOI:
10.1038/nature14980
[Indexed for MEDLINE]
Free PMC Article

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