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J Natl Cancer Inst. 2018 Oct 1;110(10):1084-1093. doi: 10.1093/jnci/djy022.

Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients.

Author information

1
Center for Medical Genetics, Ghent University, Ghent, Belgium.
2
Cancer Research Institute Ghent, Ghent, Belgium.
3
Institut Cochin, Inserm U1016, CNRS UMR 8104, Université Paris Descartes UMR-S1016, Paris, France.
4
Institut Curie, Inserm U900, Mines ParisTech, PSL Research University, Paris, France.
5
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
6
Data Mining and Modelling for Biomedicine Group, VIB Center for Inflammation Research, Ghent, Belgium.
7
Children's Cancer Research Institute, Austria.
8
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
9
Division of Hematology/Oncology, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA.
10
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.
11
Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, PA.
12
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA.
13
Centre Léon-Bérard, Laboratoire de Recherche Translationnelle, Lyon, France.
14
Department of Pathology, Istituto Giannina Gaslini, Genova, Italy.
15
Department of Experimental Pediatric Oncology, University of Cologne, Cologne, Germany.
16
University Children's Hospital Cologne, Medical Faculty, and Center for Molecular Medicine Cologne.
17
Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany.
18
Perelman School of Medicine (MDH), University of Pennsylvania, Philadelphia, PA.
19
Division of Hematology-Oncology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
20
Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
21
Department of Pediatrics, Duke University School of Medicine, Durham, NC.
22
Genetic Somatic Unit.
23
Institut Curie, Paris, France.
24
Department of Pediatric Hematology and Oncology, Ghent University Hospital, De Pintelaan, Ghent, Belgium.
25
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA.
26
Saga Medical Center KOSEIKAN, Saga, Japan.
27
Pathology Department, Medical School, University of Valencia, Valencia, Spain.
28
Medical Research Foundation INCLIVA, Valencia, Spain.
29
CIBERONC, Madrid, Spain.
30
Research Institute for Clinical Oncology Saitama Cancer Center, Saitama, Japan.
31
Seattle Children's Hospital and University of Washington, Seattle, WA.
32
Laboratory of Neuroblastoma, Onco/Haematology Laboratory, University of Padua, Pediatric Research Institute (IRP)-Città della Speranza, Padova, Italy.
33
Institut Gustave Roussy, Université Paris Sud, Paris, France.
34
Laboratory of Molecular Biology (LV), Istituto Giannina Gaslini, Genova, Italy.
35
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
36
Abramson Family Cancer Research Institute, Philadelphia, PA.
37
U830 INSERM, Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology.

Abstract

Background:

Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations.

Methods:

In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome.

Results:

In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were detected in 5.9% of patients and were associated with a 10-year survival probability of only 3.4% (95% confidence interval [CI] = 0.5% to 23.3%, two-sided P = .002). Amplifications of regions not encompassing the MYCN locus were detected in 18.1% of patients and were associated with a 10-year survival probability of only 5.8% (95% CI = 1.5% to 22.2%, two-sided P < .001).

Conclusions:

Using a unique large copy number data set of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes.

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