Loss of ALK hotspot mutations in relapsed neuroblastoma

Lisa M. Allinson, Aaron Potts, Angharad Goodman, Nick Bown, Matthew Bashton, Dean Thompson, Nermine O. Basta, Alem S. Gabriel, Michael McCorkindale, Antony Ng, Richard J. Q. McNally, Deborah A. Tweddle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


ALK is the most commonly mutated oncogene in neuroblastoma with increased mutation frequency reported at relapse. Here we report the loss of an ALK mutation in two patients at relapse and a paired neuroblastoma cell line at relapse.

ALK detection methods including Sanger sequencing, targeted next-generation sequencing and a new ALK Agena MassARRAY technique were used to detect common hotspot ALK variants in tumours at diagnosis and relapse from two high-risk neuroblastoma patients. Copy number analysis including single nucleotide polymorphism array and array comparative genomic hybridisation confirmed adequate tumour cell content in DNA used for mutation testing.

Case 1 presented with an ALK F1174L mutation at diagnosis with a variant allele frequency (VAF) ranging between 23.5-28.5%, but the mutation was undetectable at relapse. Case 2 presented with an ALK R1257Q mutation at diagnosis (VAF=39-47.4%) which decreased to <0.01% at relapse. Segmental chromosomal aberrations were maintained between diagnosis and relapse confirming sufficient tumour cell content for mutation detection. The diagnostic SKNBE1n cell line harbours an ALK F1174S mutation, which was lost in the relapsed SKNBE2c cell line.

To our knowledge, these are the first reported cases of loss of ALK mutations at relapse in neuroblastoma in the absence of ALK inhibitor therapy, reflecting intra-tumoural spatial and temporal heterogeneity. As ALK inhibitors are increasingly used in the treatment of refractory/relapsed neuroblastoma, our study highlights the importance of confirming whether an ALK mutation detected at diagnosis is still present in clones leading to relapse.
Original languageEnglish
JournalGenes, Chromosomes and Cancer
Early online date27 Aug 2022
Publication statusE-pub ahead of print - 27 Aug 2022


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