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Br J Cancer. 2018 May;118(11):1502-1512. doi: 10.1038/s41416-018-0098-6. Epub 2018 May 14.

Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study.

Author information

1
Department of Pathology, Medical School, University of Valencia/INCLIVA Biomedical Research Institute, 46010, Valencia, Spain.
2
Ciberonc, Madrid, Spain.
3
Department of Tumour Biology CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090, Vienna, Austria.
4
S2IRP: Studies and Statistics for Integrated Research and Projects CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090, Vienna, Austria.
5
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, 0372, Oslo, Norway.
6
Northern Genetics Service, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
7
Centre Léon Bérard, Laboratoire de Recherche Translationnelle, 28 rue Laennec, Lyon, 69008, France.
8
Department of Pathology, Gaslini Institute, Largo G. Gaslini 5, 16147, Genoa, Italy.
9
Cancer Cytogenetic and Molecular Cytogenetic Laboratory, Schneider Children's Medical Center of Israel, 49202, Petach Tikva, Israel.
10
Laboratory of Molecular Biology, Gaslini Institute, Largo G. Gaslini 5, 16147, Genoa, Italy.
11
Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 15006, Prague, Czech Republic.
12
Department of Paediatric Haematology-Oncology, Schneider Children's Medical Center of Israel, 49202, Petach Tikva, Israel.
13
Pediatric Oncology Unit, Hospital Universitari i Politècnic La Fe, 46026, Valencia, Spain.
14
Department of Paediatric Haematology-Oncology, Aix-Marseille University and APHM, Hôpital d' Enfants de La Timone, 13385, Marseille, France.
15
St Anna Children's Hospital and Department of Paediatrics of the Medical University, 1090, Vienna, Austria.
16
Our Lady's Children's Hospital, Crumlin, Dublin, D12 N512, Ireland.
17
Department of Paediatric Haematology-Oncology, Agia Sofia Children's Hospital Athens, 11528, Athens, Greece.
18
Department of Paediatric Medicine, Rikshospitalet, Oslo University Hospital, 0372, Oslo, Norway.
19
Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria.
20
Department of Paediatrics, Medical University Vienna, Vienna, Austria.
21
Department of Pathology, Medical School, University of Valencia/INCLIVA Biomedical Research Institute, 46010, Valencia, Spain. rosa.noguera@uv.es.
22
Ciberonc, Madrid, Spain. rosa.noguera@uv.es.
23
Department of Tumour Biology CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090, Vienna, Austria. ambros@ccri.at.

Abstract

BACKGROUND:

In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues.

METHODS:

The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH.

RESULTS:

Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 ± 0.04, >18 m: 0.67 ± 0.14, p = 0.011; metastatic: <18 m: 0.76 ± 0.15, >18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse.

CONCLUSIONS:

This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.

PMID:
29755120
PMCID:
PMC5988829
[Available on 2019-05-29]
DOI:
10.1038/s41416-018-0098-6
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