Age-dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma
Age-dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma
复制标题
DOI：
10.1002/ijc.27432
复制
发表时间：
2012-10-01
影响因子：
6.4
通讯作者：
Tonini, Gian Paolo
中科院分区：
文献类型：
--
作者：
Coco, Simona;Theissen, Jessica;Tonini, Gian Paolo
约50%的儿童神经母细胞瘤（NB）表现为转移性疾病，预后不良。然而，疾病进展变化很大，取决于患者的年龄和MYCN癌基因扩增。为了研究患者年龄在肿瘤侵袭性中的作用，我们对三组(G)转移性NBs进行了阵列- cgh和基因表达谱分析：G1、4S期患者和MYCN单拷贝（MYCN-）肿瘤；G2, 4期患者，年龄18个月，MYCN-肿瘤，预后良好；G3, 4期患者，年龄19个月，预后不良。G1以数值像差为主；相反，所有G3肿瘤都有结构重排，而G2则表现为中间模式。从G1到G2再到G3，数值变化的平均值显著降低（p < 0.01）。相反，从G1到G2再到G3，结构像差的数量呈增加趋势（p < 2.35 E-05）。值得注意的是，G3/MYCN- nb具有几个复杂的染色体内重排的特征。三组在Rho和Ras信号通路、发育与粘附、细胞周期调控、端粒酶活性等基因表达分析上均存在显著差异。结构改变的积累随着患者年龄的增长而增加，并与更具侵袭性的疾病相关。参与细胞周期和端粒酶的基因在G3中的异常表达可能是该队列患者基因组不稳定的原因。在G3/MYCN- NBs中观察到的DNA不稳定性高于MYCN扩增的G3，这也可以解释为什么患者=19个月的预后不受MYCN状态的影响。
About 50% of children with neuroblastoma (NB) show a metastatic disease and have a poor prognosis. However, disease progression is greatly variable and depends on patients' age and MYCN oncogene amplification. To investigate the role of patients' age in tumor aggressiveness, we performed array-CGH and gene expression profiles of three groups (G) of metastatic NBs: G1, stage 4S patients and MYCN single copy (MYCN-) tumors; G2, stage 4 patients, =18 months of age, MYCN- tumors and favorable outcome and G3, Stage 4 patients, =19 months with unfavorable outcome. G1 was characterized by numerical aberrations prevalently; on the contrary, all G3 tumors had structural rearrangements, whereas G2 showed an intermediate pattern. The average of numerical alterations decreased significantly from G1 to G2 to G3 (p < 0.01). Contrarily, the number of structural aberrations increased from G1 to G2 to G3 (p < 2.35 E-05). Noteworthy, G3/MYCN- NBs were characterized by several complex intrachromosome rearrangements. Expression analysis of the three groups showed significant differences in genes of Rho and Ras signaling pathways, development and adhesion, cell cycle regulation and telomerase activity. Accumulation of structural alterations increased with patients' age and was associated with a more aggressive disease. Abnormal expression of genes involved in cell cycle and telomerase in G3 may be responsible for the genomic instability in this cohort of patients. The higher DNA instability observed in G3/MYCN- NBs than in MYCN-amplified G3 may also explain why patients =19 months have a poor outcome independently by MYCN status.