Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks
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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.
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48 DS genes (10%) encode RNA binding proteins or splicing factors, and at least six splicing factors also showed DTE.
“Notably, 48 DS genes (10%; FDR=8.8×10−4) encode RNA binding proteins or splicing factors (34), with at least six splicing factors also showing DTE in ASD (MATR3), SCZ (QKI, RBM3, SRRM2, U2AF1) or both (SRSF11).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [34]
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- Authors
- Sebestyén, E., Singh, B., Miñana, B., Pagès, A., Mateo, F., Pujana, M. A., Valcárcel, J., & Eyras, E.
- Affiliations
- Universitat Pompeu Fabra (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2016-04-13
- Volume
- 26
- Issue
- 6
- Pages
- 732-744
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC4889968
- OpenAlex
- W2338046461
- Cited by
- 276
- References
- 61
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 25 · 2023: 21 · 2022: 38 · 2021: 45 · 2020: 43 · 2019: 27 · 2018: 22 · 2017: 22 · 2016: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (publishedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, cc-by-nc)
- Funders
- Ministerio de Economía y Competitividad
- European Commission
- FEDER (BIO2014-52566-R, PIE13/00022-ONCOPROFILE, PI15/00854, RD12/0036/0008)
- Consolider RNAREG (CSD2009-00080)
- Agència de Gestió d'Ajuts Universitaris i de Recerca (SGR2014-1121)
- Sandra Ibarra Foundation for Cancer (FSI2013)
- Fundación Botín
- Santander Universities Global Division
- MINECO
- AGAUR (SGR2014-364)
- AECC
- Instituto de Salud Carlos III
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- alternative splicing, RNA-binding proteins, cancer, solid tumors, MBNL1, NUMA1, copy number variation, gene expression changes, binding motifs, centrosome amplification, cell proliferation, mammary epithelial cells, undifferentiated cells
- MeSH terms
- RNA Splicing Factors, Binding Sites, Humans, Mutation, Neoplasms, Genome, Human, Gene Expression Regulation, Neoplastic, Alternative Splicing, Amino Acid Motifs, Gene Expression Profiling, Cell Proliferation, Transcriptome
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