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Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5269-5279. doi: 10.1073/pnas.1915975117. Epub 2020 Feb 21.

Pathway-guided analysis identifies Myc-dependent alternative pre-mRNA splicing in aggressive prostate cancers.

Author information

1
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095.
2
Bioinformatics Interdepartmental Graduate Program, University of California, Los Angeles, CA 90095.
3
Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
4
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263.
5
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095; owenwitte@mednet.ucla.edu xingyi@email.chop.edu.
6
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
7
Molecular Biology Institute, University of California, Los Angeles, CA 90095.
8
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.
9
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
10
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Abstract

We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known cancer driver alterations. To do so, we compiled a metadataset composed of 876 RNA-sequencing (RNA-Seq) samples from five publicly available sources representing a range of prostate phenotypes from normal tissue to drug-resistant metastases. We subjected these samples to exon-level analysis with rMATS-turbo, purpose-built software designed for large-scale analyses of splicing, and identified 13,149 high-confidence cassette exon events with variable incorporation across samples. We then developed a computational framework, pathway enrichment-guided activity study of alternative splicing (PEGASAS), to correlate transcriptional signatures of 50 different cancer driver pathways with these alternative splicing events. We discovered that Myc signaling was correlated with incorporation of a set of 1,039 cassette exons enriched in genes encoding RNA binding proteins. Using a human prostate epithelial transformation assay, we confirmed the Myc regulation of 147 of these exons, many of which introduced frameshifts or encoded premature stop codons. Our results connect changes in alternative pre-mRNA splicing to oncogenic alterations common in prostate and many other cancers. We also establish a role for Myc in regulating RNA splicing by controlling the incorporation of nonsense-mediated decay-determinant exons in genes encoding RNA binding proteins.

KEYWORDS:

Myc; PEGASAS; alternative splicing; prostate cancer; rMATS

Conflict of interest statement

Competing interest statement: O.N.W. currently has consulting, equity, and/or board relationships with Trethera Corporation, Kronos Biosciences, Sofie Biosciences, and Allogene Therapeutics. D.L.B. and Y.X. are scientific cofounders of Panorama Medicine. None of these companies contributed to or directed any of the research reported in this article.

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