Translational compensation of genomic instability in neuroblastoma.
Translational compensation of genomic instability in neuroblastoma.
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DOI：
10.1038/srep14364
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发表时间：
2015-09-24
影响因子：
4.6
通讯作者：
Quattrone A
中科院分区：
文献类型：
--
作者：
Dassi E;Greco V;Sidarovich V;Zuccotti P;Arseni N;Scaruffi P;Tonini GP;Quattrone A
癌症相关基因表达失衡通常在基因组、表观基因组和转录组水平上进行研究。鉴于翻译控制在确定细胞表型中的相关性，我们评估了翻译组，即，转录组参与翻译，作为癌症遗传不稳定性影响的描述。我们在高危神经母细胞瘤中进行了这项评估，其特征是点突变或已知癌症驱动基因的频率较低，以及存在几个节段性染色体畸变，这些畸变产生基因拷贝失衡，从而指导攻击性。因此，我们在一组代表性的高危神经母细胞瘤细胞系中整合了基因组、转录组、翻译组和miRome谱。我们确定了一些基因，其基因组的不平衡被纠正的翻译效率的补偿性适应。这些基因的转录组水平在超过一半的病例中预测预后不良，并且在其基因座中发现的基因组不平衡与其他27种肿瘤类型相同。这种稳态过程也不限于拷贝数改变的基因，因为我们显示了组蛋白基因的翻译化学计量再平衡。我们认为，这些剂量敏感的转录波动的翻译缓冲是神经母细胞瘤演变的一个潜在的驱动过程。
Cancer-associated gene expression imbalances are conventionally studied at the genomic, epigenomic and transcriptomic levels. Given the relevance of translational control in determining cell phenotypes, we evaluated the translatome, i.e., the transcriptome engaged in translation, as a descriptor of the effects of genetic instability in cancer. We performed this evaluation in high-risk neuroblastomas, which are characterized by a low frequency of point mutations or known cancer-driving genes and by the presence of several segmental chromosomal aberrations that produce gene-copy imbalances that guide aggressiveness. We thus integrated genome, transcriptome, translatome and miRome profiles in a representative panel of high-risk neuroblastoma cell lines. We identified a number of genes whose genomic imbalance was corrected by compensatory adaptations in translational efficiency. The transcriptomic level of these genes was predictive of poor prognosis in more than half of cases, and the genomic imbalances found in their loci were shared by 27 other tumor types. This homeostatic process is also not limited to copy number-altered genes, as we showed the translational stoichiometric rebalance of histone genes. We suggest that the translational buffering of fluctuations in these dose-sensitive transcripts is a potential driving process of neuroblastoma evolution.