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 anaplastic lymphoma kinase (ALK) are responsible for oncogenicity, frequently observed during relapses. A 3-year-old girl with relapsed high-risk NBL had a heterozygous ALK 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 ALK 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 ALK mutation status will be promising in future using more potent next-generation ALK inhibitors.