Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.
Br J Cancer. 2023 Apr;128(8):1559-1571. doi: 10.1038/s41416-023-02208-y. Epub 2023 Feb 17.
Genomic alterations of the anaplastic lymphoma kinase gene (ALK) occur recurrently in neuroblastoma, a pediatric malignancy of the sympathetic nervous system. However, information on their development over time has remained sparse.
ALK alterations were assessed in neuroblastomas at diagnosis and/or relapse from a total of 943 patients, covering all stages of disease. Longitudinal information on diagnostic and relapsed samples from individual patients was available in 101 and 102 cases for mutation and amplification status, respectively.
At diagnosis, ALK point mutations occurred in 10.5% of all cases, with highest frequencies in stage 4 patients <18 months. At relapse, ALK alteration frequency increased by 70%, both in high-risk and non-high-risk cases. The increase was most likely due to de novo mutations, frequently leading to R1275Q substitutions, which are sensitive to pharmacological ALK inhibition. By contrast, the frequency of ALK amplifications did not change over the course of the disease. ALK amplifications, but not mutations, were associated with poor patient outcome.
The considerably increased frequency of ALK mutations at relapse and their high prevalence in young stage 4 patients suggest surveying the genomic ALK status regularly in these patient cohorts, and to evaluate ALK-targeted treatment also in intermediate-risk patients.
间变性淋巴瘤激酶基因 (ALK) 的基因组改变在神经母细胞瘤中经常发生，这是一种起源于交感神经系统的儿童恶性肿瘤。然而，其随时间变化的发展信息仍然很少。
对来自总共 943 名患者的神经母细胞瘤进行了 ALK 改变的评估，涵盖了疾病的所有阶段。对于每个患者的诊断和/或复发样本，分别有 101 例和 102 例有纵向信息，可用于评估突变和扩增状态。
在诊断时，所有病例中有 10.5% 发生了 ALK 点突变，在 18 个月以下的 4 期患者中频率最高。在复发时，高危和非高危病例中 ALK 改变的频率均增加了 70%。增加很可能是由于新出现的突变，这些突变通常导致对药理学 ALK 抑制敏感的 R1275Q 取代。相比之下，ALK 扩增的频率在疾病过程中没有变化。ALK 扩增，但不是突变，与患者预后不良相关。
在复发时 ALK 突变的频率显著增加，在年轻的 4 期患者中也很常见，这提示在这些患者队列中定期检测基因组 ALK 状态，并评估针对 ALK 的治疗方法也适用于中危风险患者。
