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. 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. 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. 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.

中文翻译：

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MYCN非扩增性神经母细胞瘤的基因组概况和神经母细胞瘤免疫治疗策略的潜力

MYCN扩增是神经母细胞瘤（NB）中最重要的基因组特征。但是，对MYCN非扩增型NB包括低风险和中风险NB的研究有限。在这里，研究了MYCN非扩增NB的基因组特征，以鉴定用于分子分层的生物标记。分析了MYCN非扩增NB的58个全外显子组测序（WES）和48个全转录组测序（WTS）样品。41名患者携带了WES和WTS对。在MYCN非扩增NB WES数据中，MUC4（26％）中发现了最大的复发突变，其次是RBMXL3（19％），ALB（17％），MUC16和SEPD8（各占14％）。WTS分析中经常出现两种基因融合体，即CCDC32-CBX3（10％）和SAMD5-SASH1（6％），并且这些融合蛋白大多数在神经节神经母细胞瘤组织学非高危患者中发现。风险组特异性生物标志物的分析表明，在风险组之间差异表达了几个基因和基因组，并且在高风险组中倾向于激活了一些免疫相关途径。通常在60％的患者中检测到代表DNA错配修复相关突变的突变标记6和18。在肿瘤突变负荷（TMB）分析中，四名患者显示出高TMB（> 3个突变/ Mb），并且具有与MMR或同源重组相关的基因突变。除了4个TMB> 3 Mb的异常样本，高风险患者的TMB水平明显高于非高风险患者。这项研究为MYCN非扩增NB的基因组背景提供了新颖的见解。高危人群中免疫相关途径的激活以及TMB和突变特征分析的结果共同表明，有必要进行进一步研究以发现NB的潜在免疫治疗策略。