神经母细胞瘤中烙印基因的甲基化改变：对预后的影响
Altered methylation of imprinted genes in neuroblastoma: implications for prognostic refinement
影响因子:7.50000
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
摘要
神经母细胞瘤（NB）是一种复杂的疾病，当前对NB生物学的理解是有限的。基因组印记中的放松管制是恶性肿瘤的常见事件。由于印迹基因在早期胎儿的生长和发育中起着至关重要的作用，因此可以提出它们在NB发病机理中的作用。我们检查了49个差异甲基化区域（DMR）的369个NB肿瘤的DNA甲基化模式的改变，并评估了其与临床和临床和植物学特征的整体生存能力和所选择的临床和类型特征的关联。此外，进行了DNA甲基化和等位基因特异性拷贝数改变（CNA）的综合分析，以了解两个分子事件之间的相关性。确定了NB中具有异常的甲基化模式的几个刻痕区域。在> 30％的NB样品中经过甲基化损失的区域被注释到NDN，SNRPN，IGF2，MAGEL2和HTR5A的基因，以及甲基化获得的区域是NNAT，RB1和GPR1。在49个印迹DMR中的六个甲基化改变在统计学上与降低的总生存率显着相关：MiR886，RB1，NNAT/BLCAP，MAGEL2，MKRN3和INPP5F。 RB1，NNAT/BLCAP和MKRN3能够进一步对低风险的NB肿瘤进行分层，即缺乏MYCN扩增的肿瘤和11Q缺失为风险组。 NNAT/BLCAP，MAGEL2和MIR886的甲基化改变会预测风险与MYCN扩增或诊断时的11Q缺失和年龄。对等位基因特异性CNA的研究表明，在NB肿瘤中显示大多数变化的印迹区域具有真正的表观遗传变化，并且不是基础CNA的结果。在NB肿瘤中经常发生印迹区域的甲基化，并且其中一些区域中的几个地区具有独立的预后价值。因此，这些可能是潜在的重要临床表观遗传标记，以识别患有不良预后的个体。这些区域的甲基化状况与已建立的风险预测因子合并可能会进一步完善NB患者的预后。
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.