19p loss is significantly enriched in older age neuroblastoma patients and correlates with poor prognosis (Agilent-013282, dataset 1). 19p loss is significantly enriched in older age neuroblastoma patients and correlates with poor prognosis (Agilent-013282, dataset 1)

Genomic aberrations of neuroblastoma occurring in late childhood and adolescence are uncommon and still underestimated. Public DNA copy number profiles of 556 tumors (discovery set) and of 208 tumors obtained by array-CGH assay (validation set) were used to verify if 19p loss is significantly over-represented in children and adolescents. The 19p loss occurrence was separately tested within different age groups in the discovery and validation set and the resulting P values were combined and corrected by Bonferroni’s method. In both sets, the lowest age group significantly associated with 19p loss (discovery set: 20%; validation set: 35%) was 6 years. The 19p loss was considered to be a significant marker for overall survival in patients over 6 years of age. Relevant tumor suppressor genes (KEAP1, DNM2, SMARCA4, SLC44A2 and CDKN2D) and microRNAs (miR-181c, miR-27a, and mirR-199a-1) were in 19p loss. Down-regulation of DNM2, SLC44A2 and CDKN2D associated with poor patient outcome and older age. Among the recurrent NB chromosomal aberrations, only 1q gain was enriched in patients older than 6 years and was mutually exclusive respect to 19p loss. Our data demonstrate that 19p loss is a genomic biomarker of NBs diagnosed in older children that can predict clinical outcome. Overall design: This study includes 208 neuroblastoma tumors obtained by array-CGH assay were used to verify if 19p loss is significantly over-represented in children and adolescents. This subseries includes 2 neuroblastoma tumors analyzed on Agilent-013282.

发生于儿童晚期及青少年期的神经母细胞瘤基因组畸变较为罕见，且目前仍未得到足够重视。本研究使用了556份肿瘤样本的公共DNA拷贝数谱（发现集），以及通过阵列比较基因组杂交（array-CGH）技术获取的208份肿瘤样本的DNA拷贝数谱（验证集），用以验证19p缺失在儿童及青少年群体中是否显著富集。研究分别在发现集与验证集的不同年龄组中检测了19p缺失的发生情况，并通过Bonferroni校正法对所得P值进行合并与校正。在两个数据集当中，与19p缺失显著相关的最年轻年龄组均为6岁组（发现集检出率20%；验证集检出率35%）。在年龄超过6岁的患者中，19p缺失可作为总生存期的显著预后标志物。定位于19p缺失区域的相关抑癌基因包括KEAP1、DNM2、SMARCA4、SLC44A2及CDKN2D，相关微小RNA（miRNA）包括miR-181c、miR-27a以及miR-199a-1。DNM2、SLC44A2与CDKN2D的表达下调与患者不良预后及高龄显著相关。在神经母细胞瘤常见的复发性染色体畸变中，仅1q扩增在6岁以上患者中富集，且与19p缺失呈互斥关系。本研究数据表明，19p缺失可作为大龄儿童神经母细胞瘤的基因组生物标志物，用于预测患者临床结局。总体实验设计：本研究纳入通过阵列比较基因组杂交（array-CGH）技术获取的208份神经母细胞瘤样本，用以验证19p缺失在儿童及青少年群体中是否显著富集。本次亚系列分析包含2份在Agilent-013282芯片上完成检测的神经母细胞瘤样本。