Duplication of ALK F1245 missense mutation due to acquired uniparental disomy associated with aggressive progression in a patient with relapsed neuroblastoma

Recent genome-wide analysis of neuroblastoma (NBL) revealed amplification and heterozygous mutation of are responsible for oncogenicity, frequently observed during relapses. A 3-year-old girl with relapsed high-risk NBL had a heterozygous F1245L mutation at diagnosis, which became homozygous due to...

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Bibliographic Details
Published in:Oncology letters 2019-03, Vol.17 (3), p.3323-3329
Main Authors: Kimura, Shunsuke, Hasegawa, Daisuke, Yoshimoto, Yuri, Seki, Masafumi, Daida, Atsuro, Sekiguchi, Masahiro, Hirabayashi, Shinsuke, Hosoya, Yosuke, Kobayashi, Masao, Miyano, Satoru, Ogawa, Seishi, Takita, Junko, Manabe, Atsushi
Format: Article
Language:English
Subjects:
Care and treatment
Chemotherapy
Cloning
Development and progression
Gene expression
Gene mutations
Genes
Genetic aspects
Genomes
Genomics
Health aspects
Inhibitor drugs
Kinases
Mutation
Neuroblastoma
Oncology
Targeted cancer therapy
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Summary:Recent genome-wide analysis of neuroblastoma (NBL) revealed amplification and heterozygous mutation of are responsible for oncogenicity, frequently observed during relapses. A 3-year-old girl with relapsed high-risk NBL had a heterozygous F1245L mutation at diagnosis, which became homozygous due to uniparental disomy (UPD) of the entire chromosome 2, confirmed by single nucleotide polymorphism array and variant allele frequency of this mutation. The ALK inhibitor, crizotinib, failed to control the tumor and the patient died of the disease. Further genomic analysis using targeted capture sequencing for 381 genes related to pediatric cancers identified more alterations acquired at relapse, such as TSC complex subunit 2 and protein tyrosine phosphatase receptor type D. In addition to these several acquired mutations, this extremely rare duplication of mutation might explain the aggressive clinical course after relapse, because acquired UPD, resulting in the duplication of an oncogenic mutation, has been reported for various neoplasms. Although a clinical benefit of ALK inhibitors in patients with NBL has not been confirmed yet, a treatment based on the mutation status will be promising in future using more potent next-generation ALK inhibitors.
ISSN:1792-1074
1792-1082
DOI:10.3892/ol.2019.9985