神经母细胞瘤（NB）是一种复杂的疾病，目前对 NB 生物学的了解有限。基因组印记的失调是恶性肿瘤中的常见事件。由于印记基因在胎儿早期生长和发育中起着至关重要的作用，因此可以推测它们在 NB 发病机制中的作用。我们检查了 369 个 NB 肿瘤的 49 个印记差异甲基化区域 (DMR) 的 DNA 甲基化模式的变化，并评估了其与总体生存概率的关联并选择肿瘤的临床和基因组特征。此外，还对DNA甲基化和等位基因特异性拷贝数改变（CNA）进行了综合分析，以了解两个分子事件之间的相关性。在NB中鉴定出了几个具有异常甲基化模式的印记区域。超过 30% 的 NB 样品中甲基化缺失的区域是注释为 NDN、SNRPN、IGF2、MAGEL2 和 HTR5A 基因的 DMR，甲基化增加的区域是 NNAT、RB1 和 GPR1。 49 个印记 DMR 中的 6 个甲基化改变与总体生存率降低具有统计显着相关性：MIR886、RB1、NNAT/BLCAP、MAGEL2、MKRN3 和 INPP5F。 RB1、NNAT/BLCAP 和 MKRN3 能够进一步将低风险 NB 肿瘤（即缺乏 MYCN 扩增和 11q 缺失的肿瘤）分层为风险组。 NNAT/BLCAP、MAGEL2 和 MIR886 的甲基化改变预测风险，与 MYCN 扩增或 11q 缺失以及诊断时年龄无关。对等位基因特异性 CNA 的研究表明，在 NB 肿瘤中表现出大多数改变的印记区域包含真正的表观遗传变化，而不是潜在 CNA 的结果。印记区域中的异常甲基化在 NB 肿瘤中经常发生，其中一些区域具有独立的甲基化预后价值。因此，这些可以作为潜在重要的临床表观遗传标记来识别预后不良的个体。将这些区域的甲基化状态与已建立的风险预测因素结合起来可以进一步完善 NB 患者的预后。© 2024。作者。

Neuroblastoma (NB) is a complex disease, and the current understanding of NB biology is limited. Deregulation in genomic imprinting is a common event in malignancy. Since imprinted genes play crucial roles in early fetal growth and development, their role in NB pathogenesis could be suggested.We examined alterations in DNA methylation patterns of 369 NB tumours at 49 imprinted differentially methylated regions (DMRs) and assessed its association with overall survival probabilities and selected clinical and genomic features of the tumours. In addition, an integrated analysis of DNA methylation and allele-specific copy number alterations (CNAs) was performed, to understand the correlation between the two molecular events.Several imprinted regions with aberrant methylation patterns in NB were identified. Regions that underwent loss of methylation in > 30% of NB samples were DMRs annotated to the genes NDN, SNRPN, IGF2, MAGEL2 and HTR5A and regions with gain of methylation were NNAT, RB1 and GPR1. Methylation alterations at six of the 49 imprinted DMRs were statistically significantly associated with reduced overall survival: MIR886, RB1, NNAT/BLCAP, MAGEL2, MKRN3 and INPP5F. RB1, NNAT/BLCAP and MKRN3 were further able to stratify low-risk NB tumours i.e. tumours that lacked MYCN amplification and 11q deletion into risk groups. Methylation alterations at NNAT/BLCAP, MAGEL2 and MIR886 predicted risk independently of MYCN amplification or 11q deletion and age at diagnosis. Investigation of the allele-specific CNAs demonstrated that the imprinted regions that displayed most alterations in NB tumours harbor true epigenetic changes and are not result of the underlying CNAs.Aberrant methylation in imprinted regions is frequently occurring in NB tumours and several of these regions have independent prognostic value. Thus, these could serve as potentially important clinical epigenetic markers to identify individuals with adverse prognosis. Incorporation of methylation status of these regions together with the established risk predictors may further refine the prognostication of NB patients.© 2024. The Author(s).