Harmonization of Reporting of ALK Genetic Alterations in Neuroblastoma

In high-risk neuroblastoma, identification of ALK activating genetic alterations is considered for clinical decision-making at relapse or more recently in frontline treatment. The accurate diagnosis of genetic alterations requires harmonization of molecular techniques and reporting, especially when these concern inclusion criteria for clinical trials. Analysis and validation of 14 DNA samples harboring distinct ALK alterations were performed across the 21 SIOPEN (International Society of Paediatric Oncology Europe Neuroblastoma) molecular diagnostic laboratories. These included ALK mutations at or outside hotspots in the tyrosine kinase domain with variant allele frequencies (VAFs) of 1% to 91% or ALK genomic amplification. Each laboratory used their own techniques: ALK amplifications were detected by pan-genomic copy number techniques or fluorescence in situ hybridization, and ALK mutations were characterized by next-generation sequencing techniques. All laboratories correctly identified high-level ALK amplification and ALK mutations within the known hotspots with VAF >5%, with the exception of two cases. Differences in interpretation and reporting were apparent for samples harboring mutations with a VAF <5% or outside known hotspots. These results highlight the importance of standard operating procedures, standardized reporting, and the robustness of ALK genetic testing in the SIOPEN laboratories, and the need for expert discussions regarding atypical ALK alterations, to validate eligibility for ALK targeted treatment in clinical trials.

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Publication Details

Journal
Journal of Molecular Diagnostics
Published
2025-10-18
DOI
https://doi.org/10.1016/j.jmoldx.2025.09.007
Primary Topic
Neuroblastoma Research and Treatments
Type
article
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article

Harmonization of Reporting of ALK Genetic Alterations in Neuroblastoma

Sophie Cotteret, Michal Hameiri‐Grossman, Nadine Van Roy, Frank Westermann et al.
Journal of Molecular Diagnostics
Neuroblastoma Research and Treatments
article

Harmonization of Reporting of ALK Genetic Alterations in Neuroblastoma

Sophie Cotteret, Michal Hameiri‐Grossman, Nadine Van Roy, Frank Westermann, Alexandra Saint‐Charles, Yasmine Iddir, Toby N. Trahair, Paulette Barahona, Angharad Goodman, Siebe Loontiens, Olivier Delattre, Bastiaan B.J. Tops, Jennie Gaarder, Yehudit Birger, Maria Rossing, Katia Mazzocco, Hedwig E. Deubzer, Claudia Pasqualini, Aleš Vícha, Deborah A. Tweddle, Jacqueline Schoumans, Sally L. George, Angelika Eggert, Matthias Fischer, Carolina Rosswog, Jaime Font de Mora, Louis Chesler, Mario Capasso, Julien Masliah‐Planchon, Sabine Taschner‐Mandl, Valérie Combaret, Valéry Attignon, Angela Bellini, Mark J. Cowley, Klaus Beiske, Keren Shichrur, Tommy Martinsson, Sakina Zaïdi, Raghda R. Ibrahim, Jasper Vandermeulen, Elnaz Saberi-Ansari, Marie Bernkopf, Gudrun Schleiermacher, Rosa Noguera Salvá, Ángel M. Carcaboso, Charles Bobin, David R. Betts, Godelieve A.M. Tytgat
article en

Abstract

In high-risk neuroblastoma, identification of ALK activating genetic alterations is considered for clinical decision-making at relapse or more recently in frontline treatment. The accurate diagnosis of genetic alterations requires harmonization of molecular techniques and reporting, especially when these concern inclusion criteria for clinical trials. Analysis and validation of 14 DNA samples harboring distinct ALK alterations were performed across the 21 SIOPEN (International Society of Paediatric Oncology Europe Neuroblastoma) molecular diagnostic laboratories. These included ALK mutations at or outside hotspots in the tyrosine kinase domain with variant allele frequencies (VAFs) of 1% to 91% or ALK genomic amplification. Each laboratory used their own techniques: ALK amplifications were detected by pan-genomic copy number techniques or fluorescence in situ hybridization, and ALK mutations were characterized by next-generation sequencing techniques. All laboratories correctly identified high-level ALK amplification and ALK mutations within the known hotspots with VAF >5%, with the exception of two cases. Differences in interpretation and reporting were apparent for samples harboring mutations with a VAF <5% or outside known hotspots. These results highlight the importance of standard operating procedures, standardized reporting, and the robustness of ALK genetic testing in the SIOPEN laboratories, and the need for expert discussions regarding atypical ALK alterations, to validate eligibility for ALK targeted treatment in clinical trials.

Journal of Molecular DiagnosticsVol. 28(1)
Université Claude Bernard Lyon 1 (FR), Oslo University Hospital (NO), Centre National de la Recherche Scientifique (FR), Hospital Sant Joan de Déu Barcelona (ES), Institute of Cancer Research (GB), Inserm (FR), German Cancer Research Center (DE), Charles University (CZ), Heidelberg University (DE), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Sahlgrenska University Hospital (SE), Istituto Giannina Gaslini (IT), Institut Gustave Roussy (FR), Copenhagen University Hospital (DK), Rigshospitalet (DK), Children's Health Ireland at Crumlin (IE), University Hospital in Motol (CZ), German Cancer Society (DE), Schneider Children's Medical Center (IL), Children's Cancer Institute Australia (AU), Hopp Children's Cancer Center Heidelberg (DE), Cancer Research Institute Ghent (BE), St Anna Children's Hospital (AT), Newcastle upon Tyne Hospital (GB), Centre de Recherche en Cancérologie de Lyon (FR), Princess Máxima Center (NL), CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Cologne (DE), INCLIVA Health Research Institute (ES), Instituto de Investigación Sanitaria La Fe (ES), St. Anna Children's Cancer Research Institute, Institut Curie (FR), Newcastle University (GB), University of Gothenburg (SE), University of Lausanne (CH)
Openalex Percentile: Top 57%
Neuroblastoma Research and Treatments
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