The Genetics of Splicing in Neuroblastoma
The Genetics of Splicing in Neuroblastoma
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DOI：
10.1158/2159-8290.cd-14-0892
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发表时间：
2015-04-01
期刊：
影响因子：
28.2
通讯作者：
Weiss, William A.
中科院分区：
文献类型：
--
作者：
Chen, Justin;Hackett, Christopher S.;Weiss, William A.
mRNA剪接的调节是一种关键的和严格调节的细胞功能，是大多数蛋白质组多样性的基础，并且在疾病中经常被破坏。使用整合基因组学方法，我们结合了两个体细胞组织（小脑和外周神经节）的基因组数据和外显子水平的转录组数据，从转基因小鼠模型的神经母细胞瘤，肿瘤，从外周神经嵴。在这里，我们描述了剪接的数量性状基因座与差异剪接整个基因组，我们用它来识别基因与以前未知的功能内的剪接途径，并定义从头内含子剪接基序，影响剪接从数百个碱基。我们的研究结果表明，这些剪接基序代表网站的功能性复发突变，并突出新的候选基因在人类癌症，包括儿童神经母细胞瘤。意义：体细胞突变与可预测的下游影响主要是降级到编码区，其中包括不到2%的人类基因组。使用无偏的神经母细胞瘤小鼠模型的体内分析，我们已经确定了内含子剪接基序，翻译成网站的复发性体细胞突变在人类癌症。（C）2015年AACR。
Regulation of mRNA splicing, a critical and tightly regulated cellular function, underlies the majority of proteomic diversity and is frequently disrupted in disease. Using an integrative genomics approach, we combined both genomic data and exon-level transcriptome data in two somatic tissues (cerebella and peripheral ganglia) from a transgenic mouse model of neuroblastoma, a tumor that arises from the peripheral neural crest. Here, we describe splicing quantitative trait loci associated with differential splicing across the genome that we use to identify genes with previously unknown functions within the splicing pathway and to define de novo intronic splicing motifs that influence splicing from hundreds of bases away. Our results show that these splicing motifs represent sites for functional recurrent mutations and highlight novel candidate genes in human cancers, including childhood neuroblastoma.SIGNIFICANCE: Somatic mutations with predictable downstream effects are largely relegated to coding regions, which comprise less than 2% of the human genome. Using an unbiased in vivo analysis of a mouse model of neuroblastoma, we have identified intronic splicing motifs that translate into sites for recurrent somatic mutations in human cancers. (C)2015 AACR.