Loss of ALK hotspot mutations in relapsed neuroblastoma

Allinson, Lisa M., Potts, Aaron, Goodman, Angharad, Bown, Nick, Bashton, Matthew, Thompson, Dean, Basta, Nermine O., Gabriel, Alem S., McCorkindale, Michael, Ng, Antony, McNally, Richard J. Q. and Tweddle, Deborah A. (2022) Loss of ALK hotspot mutations in relapsed neuroblastoma. Genes, Chromosomes and Cancer, 61 (12). pp. 747-753. ISSN 1045-2257

Genes Chromosomes Cancer - 2022 - Allinson - Loss of ALK hotspot mutations in relapsed neuroblastoma.pdf - Published Version
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Official URL: https://doi.org/10.1002/gcc.23093


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 tumors at diagnosis and relapse from two high-risk neuroblastoma patients. Copy number analysis including single nucleotide polymorphism array and array comparative genomic hybridization confirmed adequate tumor 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% and 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 tumor cell content for mutation detection. The diagnostic SKNBE1n cell line harbors 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-tumoral 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.

Item Type: Article
Additional Information: Funding information: This work was supported by Solving Kids Cancer, Newcastle NIHR Biomedical Research Centre, Action Medical Research/Great Ormond Street Hospital Charity (GN 2390), the Children’s Cancer & Leukaemia Group (CCLG)/ Little Princess Trust (CCLGA 2017 21 & CCLGA 2019 29) and the Sir Bobby Robson Foundation. We also thank the CCLG Tissue Bank for access to DNA and tissue samples (CCLG 2015 BS 04 & 2016 BS 02 & 03), and contributing CCLG Centres, including members of the Experimental Cancer Medicine Centres Paediatric network. The CCLG Tissue Bank is funded by Cancer Research UK.
Uncontrolled Keywords: ALK, loss, mutation, neuroblastoma, relapse
Subjects: A300 Clinical Medicine
B900 Others in Subjects allied to Medicine
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Rachel Branson
Date Deposited: 06 Sep 2022 09:15
Last Modified: 27 Aug 2023 03:30
URI: https://nrl.northumbria.ac.uk/id/eprint/50035

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