Abstract
BackgroundMYCN 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.MethodsFifty-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.ResultsIn 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.ConclusionsThis 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.
Highlights
IntroductionLimited studies have been conducted on the MYCN non-amplified NB including low- and intermediate-risk NB
MYCN amplification is the most important genomic feature in neuroblastoma (NB)
The clinical features of MYCN-amplified NB have been attributed to the biological consequence of MYCN amplification
Summary
Limited studies have been conducted on the MYCN non-amplified NB including low- and intermediate-risk NB. The genomic characteristics of MYCN non-amplified NB were studied to allow for the identification of biomarkers for molecular stratification. Amplification of the MYCN oncogene is the first genetic marker reported to indicate highly aggressive and advanced-stage NB. It is observed in approximately 20% of cases and remains a powerful prognostic factor, indicating adverse clinical outcomes [3]. Despite the extensive study of the genomic characteristics of high-risk NB including MYCN-amplified tumours [4,5,6], genomic profiling of MYCN non-amplified NB, including low- and intermediate-risk NB, has been limited
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