Differential Impact of Mutations in Neuroblastoma

Purpose: The tyrosine kinase receptor anaplastic lymphoma kinase (ALK) can be abnormally activated in neuroblastoma, and somatic mutations occur in 6%-10% of patients. The differential clinical impact of these mutations has not been clearly elucidated.

Methods: Data on patients with neuroblastoma harboring mutations were retrospectively analyzed. sequencing was performed by whole-genome sequencing, hybrid-based capture of targeted exomes, or hotspot mutation profiling. The differential impact of 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 mutations was compared with wild-type

Results: Of 641 patients with neuroblastoma with status analyzed on at least one tumor sample, 103 (16%) had tumors harboring 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 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 -mutated tumors.

Conclusion: Somatic 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 mutations in this population.