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

Area of Science:

• Oncology
• Molecular Biology
• Bioinformatics

Background:

• Alternative pre-mRNA splicing is crucial for gene expression and is frequently dysregulated in cancer.
• Prostate cancer exhibits complex molecular alterations, including changes in splicing patterns.

Purpose of the Study:

• To define the landscape of alternative splicing in prostate cancer.
• To correlate alternative splicing events with known cancer driver alterations.
• To investigate the role of Myc signaling in regulating alternative splicing.

Main Methods:

• Compiled a large dataset of 876 RNA-sequencing samples from diverse prostate cancer phenotypes.
• Utilized rMATS-turbo software for large-scale exon-level splicing analysis.
• Developed PEGASAS computational framework to link splicing events with cancer driver pathways.

Main Results:

• Identified 13,149 high-confidence cassette exon splicing events.
• Discovered a correlation between Myc signaling and 1,039 cassette exons, particularly in RNA-binding protein genes.
• Validated Myc's regulation of 147 of these exons, many leading to frameshifts or premature stop codons.

Conclusions:

• Alternative splicing changes are linked to oncogenic alterations in prostate and other cancers.
• Myc signaling plays a significant role in regulating RNA splicing, including nonsense-mediated decay-determinant exons.
• This work provides insights into the functional consequences of splicing alterations in cancer.