BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.

] INSERM U830 Laboratoire de Génétique et Biologie des Cancers Paris Cedex 05 75248 France [2] Département d'Oncologie Pédiatrique Institut Curie Paris Cedex 05 75248 France

Cancer Cytogenetique and Molecular Cytogenetique Laboratory Schneider Children's Medical Center of Israel Petah Tikva Israel

Center for Medical Genetics Ghent University Hospital Ghent 9000 Belgium

Children's Cancer Research Institute St Anna Kinderkrebsforschung Vienna 1090 Austria

Département de Biologie et de Pathologie Médicales Gustave Roussy Cancer Campus Villejuif 94800 France

Department of Clinical Genetics Göteborg University Sahlgrenska University Hospital Göteborg 413 45 Sweden

Department of Haematology Oncology Istituto Giannina Gaslini Genova 16148 Italy

Department of Hematology Hospital Universitari i Politècnic La Fe Valencia 46009 Spain

Department of Human Genetics National Institute of Health Doutor Ricardo Jorge Lisbon 1649 016 Portugal

Department of Paediatric Haematology and Oncology Charles University and University Hospital Motol Prague 15008 Czech Republic

Department of Paediatric Oncology Southampton General Hospital Southampton S016 6YD UK

Department of Pathology Istituto Giannina Gaslini Genova 16148 Italy

Department of Pathology Medical School of Valencia University of Valencia Valencia 46010 Spain

Department of Pathology Oslo University Hospital Rikshopitalet Oslo 0424 Norway

Epidemiology Biostatistics and Committees Unit Istituto Giannina Gaslini Genova 16148 Italy

Institute of Electronics Computer and Telecommunication Engineering National Research Council Genova 16149 Italy

Laboratoire de Recherche Translationnelle Centre Léon Bérard Lyon 69008 France

Laboratory of Neuroblastoma Onco Haematology Laboratory University of Padua Pediatric Research Institute Città della Speranza Corso Stati Uniti 4 Padova 35127 Italy

Northern Genetics Service Newcastle upon Tyne NEI 3 BZ UK

Northern Institute for Cancer Research Newcastle University Newcastle NE2 4HH UK

Pediatric Oncology Research Unit Lausanne University Hospital Lausanne 1011 Switzerland

Unité de Génétique Somatique et Cytogénétique Institut Curie Paris Cedex 05 75248 France

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Ganglioneuroblastoma in children

Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study