Differential Impact of <i>ALK</i> Mutations in Neuroblastoma.

Abstract

The tyrosine kinase receptor anaplastic lymphoma kinase (ALK) can be abnormally activated in neuroblastoma, and somatic <i>ALK</i> mutations occur in 6%-10% of patients. The differential clinical impact of these mutations has not been clearly elucidated. Data on patients with neuroblastoma harboring <i>ALK</i> mutations were retrospectively analyzed. <i>ALK</i> sequencing was performed by whole-genome sequencing, hybrid-based capture of targeted exomes, or hotspot <i>ALK</i> mutation profiling. The differential impact of <i>ALK</i> mutation site on clinical characteristics, response to treatment, and survival was analyzed. In a subgroup of patients with locoregional neuroblastoma diagnosed after 2014, the impact of all <i>ALK</i> mutations was compared with wild-type <i>ALK.</i> Of 641 patients with neuroblastoma with <i>ALK</i> status analyzed on at least one tumor sample, 103 (16%) had tumors harboring <i>ALK</i> mutations. Mutations existed across all ages (birth to 67.8 years), stages (30% locoregional and 70% metastatic), and risk groups (20%, 11%, and 69% with low-, intermediate-, and high-risk disease, respectively). Mutation sites included F1174 (51%), R1275 (29%), R1245 (10%), and others (10%). Mutation site was not prognostic for progression-free survival or overall survival in the entire cohort, high-risk subgroup, or locoregional subgroup. Locoregional tumors with any <i>ALK</i> mutation were generally invasive: L2 by International Neuroblastoma Research Group staging in 30/31 patients with a 2-year progression-free survival (59%, 95% CI, 37.4 to 80.5) that was inferior to historical controls. This observation was corroborated in the post-2014 subgroup in which gross total resection was less likely for <i>ALK</i>-mutated tumors. Somatic <i>ALK</i> mutations are present across all stages and risk groups of neuroblastoma. No specific mutation carries differential prognostic significance. Locoregional neuroblastoma has an invasive phenotype when harboring somatic <i>ALK</i> mutations in this population.