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Lookup NU author(s): Angharad Goodman, Professor Deborah TweddleORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 Association for Molecular Pathology and American Society for Investigative Pathology. 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.
Author(s): Saint-Charles A, Masliah-Planchon J, Saberi-Ansari E, Bellini A, Bernkopf M, Font de Mora J, Noguera R, Van Roy N, Goodman A, Vicha A, Attignon V, Combaret V, Beiske K, Martinsson T, Schoumans J, Rossing M, Tops B, Westermann F, Cotteret S, Fischer M, Birger Y, Mazzocco K, Chesler L, Betts D, Cowley M, Capasso M, Bobin C, Iddir Y, Zaidi S, Carcaboso AM, Vandermeulen J, Loontiens S, Gaarder J, Ibrahim RR, Rosswog C, Hameiri-Grossman M, Shichrur K, Trahair T, Barahona P, Eggert A, Deubzer HE, Delattre O, Pasqualini C, George S, Tytgat G, Tweddle DA, Taschner-Mandl S, Schleiermacher G
Publication type: Article
Publication status: Published
Journal: Journal of Molecular Diagnostics
Year: 2026
Volume: 28
Issue: 1
Pages: 27-38
Print publication date: 01/01/2026
Online publication date: 17/10/2025
Acceptance date: 23/09/2025
Date deposited: 22/12/2025
ISSN (print): 1525-1578
ISSN (electronic): 1943-7811
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.jmoldx.2025.09.007
DOI: 10.1016/j.jmoldx.2025.09.007
PubMed id: 41110766
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