Originally published as JCO Early Release 10.1200/JCO.2008.16.0630 on January 26 2009

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Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma

Isabelle Janoueix-Lerosey, Gudrun Schleiermacher, Evi Michels, Véronique Mosseri, Agnès Ribeiro, Delphine Lequin, Joëlle Vermeulen, Jérôme Couturier, Michel Peuchmaur, Alexander Valent, Dominique Plantaz, Hervé Rubie, Dominique Valteau-Couanet, Caroline Thomas, Valérie Combaret, Raphaël Rousseau, Angelika Eggert, Jean Michon, Frank Speleman, Olivier Delattre

From L'Institut National de la Santé et de la Recherche Médicale (INSERM) U830, Laboratoire de Génétique et Biologie des Cancers; Institut Curie, Département de Pédiatrie; Service de Biostatistiques, Unité de Génétique Somatique, and Unité de Cytogénétique; Hôpital Robert Debré, Service de Pathologie, Paris; Institut Gustave Roussy, Département de Biologie et de Pathologie Médicales, Service de Pathologie Moleculaire; Département de Pédiatrie, Villejuif; Centre Hospitalier Universitaire, Service Hématologie Infantile, Grenoble; Hôpital des Enfants, Unité d'Hémato-Oncologie Pédiatrique, Toulouse; Centre Hospitalier Régional, Service Hémato-Oncologie Infantile, Nantes; Centre Léon Bérard, Laboratoire d'Oncologie Moléculaire; Département de Pédiatrie, Lyon, France; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; and University Children's Hospital of Essen, Department of Paediatric Oncology and Haematology, Essen, Germany.

Corresponding author: Olivier Delattre, INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 26 rue d'Ulm, 75248 Paris Cedex 05, France; e-mail: olivier.delattre{at}curie.fr.

Purpose For a comprehensive overview of the genetic alterations of neuroblastoma, their association and clinical significance, we conducted a whole-genome DNA copy number analysis.

Patients and Methods A series of 493 neuroblastoma (NB) samples was investigated by array-based comparative genomic hybridization in two consecutive steps (224, then 269 patients).

Results Genomic analysis identified several types of profiles. Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. Patients with both numerical and segmental abnormalities clearly shared the higher risk of relapse of segmental-only patients. In a multivariate analysis, taking into account the genomic profile, but also previously described individual genetic and clinical markers with prognostic significance, the presence of segmental alterations with (HR, 7.3; 95% CI, 3.7 to 14.5; P < .001) or without MYCN amplification (HR, 4.5; 95% CI, 2.4 to 8.4; P < .001) was the strongest predictor of relapse; the other significant variables were age older than 18 months (HR, 1.8; 95% CI, 1.2 to 2.8; P = .004) and stage 4 (HR, 1.8; 95% CI, 1.2 to 2.7; P = .005). Finally, within tumors showing segmental alterations, stage 4, age, MYCN amplification, 1p and 11q deletions, and 1q gain were independent predictors of decreased overall survival.

Conclusion The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.

I.J.-L. and G.S. contributed equally to this work.

Supported by grants from the Institut National de la Santé et de la Recherche Médicale and the Ligue Nationale contre le Cancer (Equipe labellisée). Construction of the BAC/PAC array was supported by grants from the Carte d'Identité des Tumeurs/Program of the Ligue Nationale Contre le Cancer. Belgian array-CGH results were obtained by support of the Stichting tegen Kanker and Specific Targeted Research Project. E.M. is supported by the concerted research fund (GOA, No. 12051203). J.V. is supported by the Belgian Kids' Fund.

Presented in part by I.J.-L. at the Translational Genomics In Neuroblastoma-2/Therapeutically Applicable Research to Generate Effective Treatments Initiative meeting, October 1-2, 2007, Rockville, MD, and at Advances in Neuroblastoma Research 2008, May 21-24, 2008, Chiba, Japan; and by G.S. at the 39th Annual Congress of International Society of Pediatric Oncology, November 1-3, 2007, Mumbai, India.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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