Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
Transl Oncol. 2013 Aug 1;6(4):447-57. doi: 10.1593/tlo.13112. Print 2013 Aug.
Amplification of the MYCN oncogene is strongly associated with poor prognosis in neuroblastoma (NB). In addition to MYCN amplification, many studies have focused on identifying patients with a poor prognosis based on gene expression profiling. The majority of prognostic signatures today are comprised of large gene lists limiting their clinical application. In addition, although of prognostic significance, most of these signatures fail to identify cellular processes that can explain their relation to prognosis. Here, we determined prognostically predictive genes in a data set containing 251 NBs. Gene Ontology analysis was performed on significant genes with a positive hazard ratio to search for cellular processes associated with poor prognosis. An enrichment in ribonucleoproteins (RNPs) was found. Genes involved in the stabilization and formation of the central small nucleolar RNP (snoRNP) complex were scrutinized using a backward conditional Cox regression resulting in an snoRNP signature consisting of three genes: DKC1, NHP2, and GAR1. The snoRNP signature significantly and independently predicted prognosis when compared to the established clinical risk factors. Association of snoRNP protein expression and prognosis was confirmed using tissue micro-arrays. Knockdown of snoRNP expression in NB cell lines resulted in reduced telomerase activity and an increase in anaphase bridge frequency. In addition, in patient material, expression of the snoRNP complex was significantly associated with telomerase activity, occurrence of segmental aberrations, and expression-based measurements of chromosomal instability. Together, these results underscore the prognostic value of snoRNP complex expression in NB and suggest a role for snoRNPs in telomere maintenance and genomic stability.
MYCN 癌基因扩增与神经母细胞瘤（NB）的预后不良密切相关。除了 MYCN 扩增外，许多研究还集中在基于基因表达谱识别预后不良的患者。如今，大多数预后标志物都是由限制其临床应用的大型基因列表组成的。此外，尽管这些标志物具有预后意义，但大多数都未能确定可以解释其与预后之间关系的细胞过程。在这里，我们在包含 251 个 NB 的数据集确定了具有预后预测价值的基因。对具有正风险比的显著基因进行了基因本体论分析，以寻找与预后不良相关的细胞过程。发现富含核糖核蛋白（RNP）。使用后向条件 Cox 回归对涉及中央小核仁 RNP（snoRNP）复合物稳定和形成的基因进行了详细研究，得出了由三个基因组成的 snoRNP 标志物：DKC1、NHP2 和 GAR1。与既定的临床危险因素相比，snoRNP 标志物在预测预后方面具有显著的独立作用。使用组织微阵列证实了 snoRNP 蛋白表达与预后的关联。NB 细胞系中 snoRNP 表达的敲低导致端粒酶活性降低和后期桥频率增加。此外，在患者材料中，snoRNP 复合物的表达与端粒酶活性、片段性异常的发生以及基于染色体不稳定性的表达测量显著相关。这些结果共同强调了 snoRNP 复合物在 NB 中的预后价值，并表明 snoRNPs 在端粒维持和基因组稳定性中起作用。
