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Science. 2018 Dec 7;362(6419):1165-1170. doi: 10.1126/science.aat6768.

A mechanistic classification of clinical phenotypes in neuroblastoma.

Author information

1
Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany.
2
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
3
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
4
Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany.
5
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany.
6
NEO New Oncology GmbH, Cologne, Germany.
7
Division of Neuroblastoma Genomics (B087), German Cancer Research Center, and Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany.
8
Division of Pediatric Neurooncology, German Cancer Research Center, and Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany.
9
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
10
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
11
Center for Medical Genetics, Ghent University, Ghent, Belgium.
12
Interdisciplinary Research Centre in Biomedical Materials (IRCBM), COMSATS University Islamabad, Lahore Campus, Lahore, Pakistan.
13
Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
14
German Cancer Consortium (DKTK), Heidelberg, Germany.
15
Berlin Institute of Health, Berlin, Germany.
16
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
17
Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
18
Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
19
Department of Diagnostic and Interventional Radiology, University Hospital of Cologne, Cologne, Germany.
20
Department of Nuclear Medicine, University of Cologne, Cologne, Germany.
21
Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
22
Computer Science, TU Dortmund, Dortmund, Germany.
23
Computing Center, University of Cologne, Cologne, Germany.
24
Department of Informatics, University of Cologne, Cologne, Germany.
25
Kiel Pediatric Tumor Registry, Department of Pediatric Pathology, University of Kiel, Kiel, Germany.
26
Department of Pathology, University of Cologne, Cologne, Germany.
27
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute (UPCI), Hillman Cancer Center, Pittsburgh, PA, USA.
28
German Cancer Research Center (DKFZ), Heidelberg, Germany.
29
Department of Medical Oncology, West German Cancer Center Essen, University of Duisburg-Essen, Essen, Germany.
30
Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany. matthias.fischer@uk-koeln.de.

Abstract

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance-negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.

PMID:
30523111
DOI:
10.1126/science.aat6768
[Indexed for MEDLINE]

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