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首页> 美国卫生研究院文献>Oncology Letters >Duplication of ALK F1245 missense mutation due to acquired uniparental disomy associated with aggressive progression in a patient with relapsed neuroblastoma
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Duplication of ALK F1245 missense mutation due to acquired uniparental disomy associated with aggressive progression in a patient with relapsed neuroblastoma

机译：复发性神经母细胞瘤患者中由于获得性单亲二体性与侵袭性进展相关而导致的ALK F1245错义突变重复

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摘要

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.
机译：最近对神经母细胞瘤（NBL）进行的全基因组分析显示，间变性淋巴瘤激酶（ALK）的扩增和杂合突变是致癌性的原因，经常在复发期间观察到。一名复发性高危NBL的3岁女孩在诊断时出现了杂合性ALK F1245L突变，由于整个2号染色体的单亲二体性（UPD）而变成了纯合子，这一点已通过单核苷酸多态性阵列和该基因的等位基因频率证实突变。 ALK抑制剂克唑替尼无法控制肿瘤，患者死于该病。使用针对儿童疾病的381个基因的靶向捕获序列进行的进一步基因组分析，确定了复发时获得的更多改变，例如TSC复合亚基2和蛋白酪氨酸磷酸酶受体D型。除了这些获得的几个突变外，这种极罕见的ALK突变重复可能解释了复发后的侵袭性临床过程，因为据报道，对于各种肿瘤，获得性UPD会导致致癌突变的重复。尽管尚未证实ALK抑制剂在NBL患者中的临床益处，但将来使用更有效的下一代ALK抑制剂进行基于ALK突变状态的治疗将很有希望。

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