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Updated: Mar 21, 2026
An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues
Published on: April 5, 2018
Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant
Endre Sebestyén1, Babita Singh1, Belén Miñana2
1Universitat Pompeu Fabra, E08003 Barcelona, Spain;
Abstract:
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.
Insights
This study reveals widespread RNA-binding protein (RBP) gene alterations in cancer, uncovering novel splicing networks, including MBNL1 and NUMA1, that drive tumor progression and potentially cancer development.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Alternative splicing, regulated by RNA-binding proteins (RBPs), affects most eukaryotic genes.
- The role of alternative splicing in human diseases, especially cancer, is an emerging area of research.
Purpose of the Study:
- To systematically analyze alterations in RNA-binding protein (RBP) genes and their associated alternative splicing changes in human solid tumors.
- To identify novel splicing networks and their contribution to cancer development and progression.
Main Methods:
- Analysis of mutation, copy number, and gene expression data for 1348 RBP genes across 11 solid tumor types.
- Investigation of alternative splicing changes and RBP binding motif enrichment in alternatively spliced sequences.
- Functional validation of NUMA1 alternative splicing in vitro.
Main Results:
- Widespread alterations in RBP gene expression, including novel mutations and copy number variations, were observed in cancer.
- Alternative splicing patterns in several tumors mimicked those of undifferentiated cells, predicted to be controlled by MBNL1.
- NUMA1 alternative splicing was linked to increased cell proliferation and centrosome amplification in mammary epithelial cells.
Conclusions:
- The study uncovers novel splicing networks involving RBPs that are altered in cancer.
- These splicing alterations, particularly those involving MBNL1 and NUMA1, may contribute to cancer development and progression.
- Altered splicing patterns in cancer can recapitulate features of undifferentiated cells.
