Department of Paediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China.
Department of Paediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Br J Cancer. 2024 May;130(11):1841-1854. doi: 10.1038/s41416-024-02666-y. Epub 2024 Mar 29.
Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown.
A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis.
We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively.
We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.
尽管对 MYCN 扩增神经母细胞瘤进行了广泛的研究，但在非扩增 MYCN 的病例中仍存在显著的未满足的临床需求。特别是，非扩增 MYCN 人群中的异质性程度尚不清楚。
在基因表达综合数据库（GEO）和 ArrayExpress 中鉴定了来自 16 个数据集的总共 1566 个样本。通过 ConsensusClusterPlus 分析对亚型进行特征描述。根据多类对包，从单样本预测器构建独立的分组预测因子。使用免疫组织化学和 CIBERSORTx 分析验证发现。
我们证明，非扩增 MYCN 神经母细胞瘤是异质的，可以根据其转录特征分为 3 个亚组。在这些亚组中，亚组 2 的预后最差，该亚组显示出一种“MYCN”特征，可能是由 Aurora Kinase A（AURKA）的过表达诱导的；而亚组 3 的特征是“炎症”基因特征。这种亚型分类的临床意义重大，因为每个亚型都表现出独特的预后和对研究性治疗的易感性。总共鉴定出 420 个基因作为独立的亚组预测因子，训练数据集和测试数据集的平均平衡准确性分别为 0.93 和 0.84。
我们提出，转录亚分型可能会增强非扩增 MYCN 神经母细胞瘤患者的精确预后和治疗分层。
