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Quality Assessment of Genetic Markers Used for Therapy Stratification

I.M. Ambros, J. Benard, M. Boavida, N. Bown, H. Caron, V. Combaret, J. Couturier, C. Darnfors, O. Delattre, J. Freeman-Edward, C. Gambini, N. Gross, C.M. Hattinger, A. Luegmayr, J. Lunec, T. Martinsson, K. Mazzocco, S. Navarro, R. Noguera, S. O’Neill, U. Pötschger, S. Rumpler, F. Speleman, G.P. Tonini, A. Valent, N. Van Roy, G. Amann, B. De Bernardi, P. Kogner, R. Ladenstein, J. Michon, A.D.J. Pearson, P.F. Ambros

From the Children’s Cancer Research Institute, St Anna Kinderspital, and Department of Pathology, University of Vienna, Vienna, Austria; Unité des Marqueurs Génétiques des Cancers, Institut Gustave Roussy, Villejuif; Unité d’Oncologie Moléculaire, Centre Léon-Bérard, Lyon; Service de Génétique and Département de Pédiatrie, Section Médicale; and Institut Nationale de la Santé et de la Recherche Médicale U509 Pathologie Moléculaire des Cancers, Section de Recherche, Institut Curie, Paris, France; Centro de Genética Humana, Instituto Nacional de Saude, Lisboa, Portugal; Division of Human Genetics and Cancer Research Unit, University School, University of Newcastle upon Tyne; Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; Institute of Human Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, the Netherlands; Onco-Hematology Laboratory, Pediatrics Department, University Hospital Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Department of Clinical Genetics, Sahlgrenska University Hospital East, Gothenburg; Woman and Child Health, Childhood Cancer Research Unit, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden; Laboratory of Tumor Genetics, National Institute for Cancer Research; Hematology-Oncology Department and Laboratory of Anatomic Pathology, Giannina Gaslini Children’s Hospital, Genoa, Italy; Department of Pathology, University of Valencia, Valencia, Spain; and Center for Medical Genetics-OK5, University of Ghent, Ghent, Belgium.

Address reprint requests to Inge M. Ambros, MD, and Peter F. Ambros, PhD, Children’s Cancer Research Institute, Kinderspitalgasse 6, A-1090 Vienna, Austria; email: ambros{at}ccri.univie.ac.at.

Purpose: Therapy stratification based on genetic markers is becoming increasingly important, which makes commitment to the highest possible reliability of the involved markers mandatory. In neuroblastic tumors, amplification of the MYCN gene is an unequivocal marker that indicates aggressive tumor behavior and is consequently used for therapy stratification. To guarantee reliable and standardized quality of genetic features, a quality-assessment study was initiated by the European Neuroblastoma Quality Assessment (ENQUA; connected to International Society of Pediatric Oncology) Group.

Materials and Methods: One hundred thirty-seven coded specimens from 17 tumors were analyzed in 11 European national/regional reference laboratories using molecular techniques, in situ hybridization, and flow and image cytometry. Tumor samples with divergent results were re-evaluated.

Results: Three hundred fifty-two investigations were performed, which resulted in 23 divergent findings, 17 of which were judged as errors after re-evaluation. MYCN analyses determined by Southern blot and in situ hybridization led to 3.7% and 4% of errors, respectively. Tumor cell content was not indicated in 32% of the samples, and 11% of seemingly correct MYCN results were based on the investigation of normal cells (eg, Schwann cells). Thirty-eight investigations were considered nonassessable.

Conclusion: This study demonstrated the importance of revealing the difficulties and limitations for each technique and problems in interpreting results, which are crucial for therapeutic decisions. Moreover, it led to the formulation of guidelines that are applicable to all kinds of tumors and that contain the standardization of techniques, including the exact determination of the tumor cell content. Finally, the group has developed a common terminology for molecular-genetic results.

Supported by the Directorate-General V, European Comission (Luxembourg, Belgium, no. SOC 98 201284 05F02), the Austrian Federal Ministry of Education, Science and Culture (Vienna, GZ 70.041/2-Pr/4/99), the Forschungsintitut für krebskranke Kinder im St Anna Kinderspital (Vienna, Austria), and the Associazione Italiana per la Lotta al Neuroblastoma (Genoa, Italy).

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