Sebestyén Endre, Singh Babita, Miñana Belén, Pagès Amadís, Mateo Francesca, Pujana Miguel Angel, Valcárcel Juan, Eyras Eduardo
Universitat Pompeu Fabra, E08003 Barcelona, Spain;
Universitat Pompeu Fabra, E08003 Barcelona, Spain; Centre for Genomic Regulation, E08003 Barcelona, Spain;
Genome Res. 2016 Jun;26(6):732-44. doi: 10.1101/gr.199935.115. Epub 2016 Apr 13.
Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. We systematically analyzed mutation, copy number, and gene expression patterns of 1348 RNA-binding protein (RBP) genes in 11 solid tumor types, together with alternative splicing changes in these tumors and the enrichment of binding motifs in the alternatively spliced sequences. Our comprehensive study reveals widespread alterations in the expression of RBP genes, as well as novel mutations and copy number variations in association with multiple alternative splicing changes in cancer drivers and oncogenic pathways. Remarkably, the altered splicing patterns in several tumor types recapitulate those of undifferentiated cells. These patterns are predicted to be mainly controlled by MBNL1 and involve multiple cancer drivers, including the mitotic gene NUMA1 We show that NUMA1 alternative splicing induces enhanced cell proliferation and centrosome amplification in nontumorigenic mammary epithelial cells. Our study uncovers novel splicing networks that potentially contribute to cancer development and progression.
可变剪接受多种RNA结合蛋白调控，并影响大多数真核基因的表达。然而，这一过程在人类疾病尤其是癌症中的作用才刚刚开始被揭示。我们系统地分析了11种实体瘤类型中1348个RNA结合蛋白（RBP）基因的突变、拷贝数和基因表达模式，以及这些肿瘤中的可变剪接变化和可变剪接序列中结合基序的富集情况。我们的综合研究揭示了RBP基因表达的广泛改变，以及与癌症驱动基因和致癌途径中多种可变剪接变化相关的新突变和拷贝数变异。值得注意的是，几种肿瘤类型中改变的剪接模式重现了未分化细胞的模式。这些模式预计主要由MBNL1控制，并涉及多个癌症驱动基因，包括有丝分裂基因NUMA1。我们表明，NUMA1可变剪接在非致瘤性乳腺上皮细胞中诱导细胞增殖增强和中心体扩增。我们的研究揭示了可能有助于癌症发生和发展的新剪接网络。
