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Background   MYCN  amplification is the most important genomic feature in neuroblastoma (NB). However, limited studies have been conducted on the  MYCN  non-amplified NB including low- and intermediate-risk NB. Here, the genomic characteristics of  MYCN  non-amplified NB were studied to allow for the identification of biomarkers for molecular stratification.    Methods  Fifty-eight whole exome sequencing (WES) and forty-eight whole transcriptome sequencing (WTS) samples of  MYCN  non-amplified NB were analysed. Forty-one patients harboured WES and WTS pairs .Results  In the  MYCN  non-amplified NB WES data, maximum recurrent mutations were found in  MUC4  (26%), followed by  RBMXL3  (19%),  ALB  (17%), and  MUC16  and  SEPD8  (14% each). Two gene fusions,  CCDC32 - CBX3  (10%) and  SAMD5 - SASH1  (6%), were recurrent in WTS analysis, and these fusions were detected mostly in non-high-risk patients with ganglioneuroblastoma histology. Analysis of risk-group-specific biomarkers showed that several genes and gene sets were differentially expressed between the risk groups, and some immune-related pathways tended to be activated in the high-risk group. Mutational signatures 6 and 18, which represent DNA mismatch repair associated mutations, were commonly detected in 60% of the patients. In the tumour mutation burden (TMB) analysis, four patients showed high TMB (> 3 mutations/Mb), and had mutations in genes related to either MMR or homologous recombination. Excluding four outlier samples with TMB > 3 Mb, high-risk patients had significantly higher levels of TMB compared with the non-high-risk patients.    Conclusions  This study provides novel insights into the genomic background of  MYCN  non-amplified NB. Activation of immune-related pathways in the high-risk group and the results of TMB and mutational signature analyses collectively suggest the need for further investigation to discover potential immunotherapeutic strategies for NB.

Genomic profile of MYCN non-amplified neuroblastoma and potential for immunotherapeutic strategies in neuroblastoma