印记基因甲基化异常在神经母细胞瘤中的变化：对预后优化的启示

Altered methylation of imprinted genes in neuroblastoma: implications for prognostic refinement

Journal of Translational Medicine

影响因子:7.5

分区:医学2区 Top / 医学：研究与实验2区

发表日期:2024 Aug 31

作者: Medha Suman, Maja Löfgren, Susanne Fransson, Jewahri Idris Yousuf, Johanna Svensson, Anna Djos, Tommy Martinsson, Per Kogner, Teresia Kling, Helena Carén

DOI: 10.1186/s12967-024-05634-5

摘要

神经母细胞瘤（NB）是一种复杂的疾病，目前对其生物学的理解有限。基因组印记的失调在恶性肿瘤中是一种常见事件。由于印记基因在早期胎儿生长和发育中发挥关键作用，因此推测其在NB发病机制中的作用。我们对369例NB肿瘤在49个印记差异甲基化区域（DMRs）中的DNA甲基化模式进行了分析，并评估其与患者的总生存概率及部分临床和基因组特征的关系。此外，还进行了DNA甲基化与等位基因特异性拷贝数变异（CNAs）的整合分析，以理解两者之间的相关性。研究发现多个印记区域在NB中表现出异常甲基化。其中，甲基化丧失的区域（>30%的样本）包括标记于NDN、SNRPN、IGF2、MAGEL2和HTR5A的DMRs，而甲基化获得的区域包括NNAT、RB1和GPR1。在49个印记DMRs中，有6个区域的甲基化变化与总生存率的显著降低相关：MIR886、RB1、NNAT/BLCAP、MAGEL2、MKRN3和INPP5F。RB1、NNAT/BLCAP和MKRN3还能对缺乏MYCN扩增和11q缺失的低风险NB肿瘤进行风险分层。NNAT/BLCAP、MAGEL2和MIR886的甲基化变化独立于MYCN扩增或11q缺失以及诊断年龄而预测风险。对等位基因特异性CNAs的研究表明，表现出最多变化的印记区域实际上存在真正的表观遗传变化，而非仅由底层CNAs引起。印记区域的异常甲基化在NB中频繁发生，且部分区域具有独立的预后价值。这些区域可能成为具有临床意义的表观遗传标志，用于识别预后不良的患者。结合这些区域的甲基化状态与已建立的风险预测指标，有望进一步优化NB患者的预后评估。

Abstract

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.