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Unequivocal Delineation of Clinicogenetic Subgroups and Development of a New Model for Improved Outcome Prediction in Neuroblastoma

Jo Vandesompele, Michael Baudis, Katleen De Preter, Nadine Van Roy, Peter Ambros, Nick Bown, Christian Brinkschmidt, Holger Christiansen, Valérie Combaret, Maria astowska, James Nicholson, Anne O'Meara, Dominique Plantaz, Raymond Stallings, Bénédicte Brichard, Caroline Van den Broecke, Sylvia De Bie, Anne De Paepe, Geneviève Laureys, Frank Speleman

From the Center for Medical Genetics, Department of Pathology, N. Goormaghtigh Institute for Pathology, Department of Pediatric Hematology and Oncology, Ghent University Hospital, Ghent; Department of Pediatric Hematology and Oncology, Cliniques St Luc, Université Catholique de Louvain, Brussels, Belgium; Department of Pathology, Stanford University Medical Center, Stanford, CA; Medizinische Klinik und Poliklinik V der Universität Heidelberg, Heidelberg; Gemeinschaftspraxis Pathologie, Am Fuchsengraben 3, Starnberg; Universitätskinderklinik, Marburg, Germany; Children's Cancer Research Institute, St Anna Kinderspital, Vienna, Austria; Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne; Addenbrookes Hospital, Cambridge, United Kingdom; Centre d'Oncologie Génétique, Centre Léon Bérard, Lyon; Department of Pediatrics, University Hospital Center, Grenoble, France; Department of Oncology, Our Lady's Hospital for Sick Children, and National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Dublin, Ireland

Address reprint requests to Jo Vandesompele, Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, MRB, De Pintelaan 185, B-9000 Ghent, Belgium; e-mail: Joke.Vandesompele{at}UGent.be

PURPOSE: Neuroblastoma is a genetically heterogeneous pediatric tumor with a remarkably variable clinical behavior ranging from widely disseminated disease to spontaneous regression. In this study, we aimed for comprehensive genetic subgroup discovery and assessment of independent prognostic markers based on genome-wide aberrations detected by comparative genomic hybridization (CGH).

MATERIALS AND METHODS: Published CGH data from 231 primary untreated neuroblastomas were converted to a digitized format suitable for global data mining, subgroup discovery, and multivariate survival analyses.

RESULTS: In contrast to previous reports, which included only a few genetic parameters, we present here for the first time a strategy that allows unbiased evaluation of all genetic imbalances detected by CGH. The presented approach firmly established the existence of three different clinicogenetic subgroups and indicated that chromosome 17 status and tumor stage were the only independent significant predictors for patient outcome. Important new findings were: (1) a normal chromosome 17 status as a delineator of a subgroup of presumed favorable-stage tumors with highly increased risk; (2) the recognition of a survivor signature conferring 100% 5-year survival for stage 1, 2, and 4S tumors presenting with whole chromosome 17 gain; and (3) the identification of 3p deletion as a hallmark of older age at diagnosis.

CONCLUSION: We propose a new regression model for improved patient outcome prediction, incorporating tumor stage, chromosome 17, and amplification/deletion status. These findings may prove highly valuable with respect to more reliable risk assessment, evaluation of clinical results, and optimization of current treatment protocols.

Supported by BOF-grant 011F1200 and 011B4300, GOA-grant 12051203, FWO-grant G.0028.00 and VEO-grant 011V1302. Katleen De Preter is an aspirant with the Fund for Scientific Research Flanders (FWO-Vlaanderen). Nadine Van Roy is a post-doctoral researcher with the FWO. Jo Vandesompele is supported by a post-doctoral grant from the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT).

Presented in part at the Advances in Neuroblastoma Research Meeting, Paris, France, June 17-19, 2002, and at the 8th European Workshop on Cytogenetics and Molecular Genetics of Human Solid Tumours, Barcelona, Spain, September 12-15, 2002.

This text presents research results of the Belgian program of Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming.

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

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