Revealing the Determinants of Widespread Alternative Splicing Perturbation in Cancer

Area of Science:

• Genomics
• Cancer Biology
• Bioinformatics

Background:

• Alternative splicing generates functional diversity crucial for cancer.
• Mechanisms linking cancer mutations to splicing alterations are largely unknown.

Purpose of the Study:

• To develop a network-based strategy to link somatic mutations with cancer-specific splicing events.
• To investigate the functional impact of mutation-driven splicing perturbations across cancer types.

Main Methods:

• Developed DrAS-Net, a network-based strategy.
• Analyzed over 2.5 million variants across 33 cancer types.
• Inferred functional impact of deregulated splicing targets.

Main Results:

• Identified over 40,000 driver variant candidates and 80,000 splicing targets.
• Observed reduced immune gene expression and increased proliferation markers in tumors with splicing perturbations.
• Found distinct splicing alterations for different mutations within the same gene.
• Stratified 10,000 patients into subtypes with distinct clinical features, including survival rates.

Conclusions:

• Single-nucleotide changes can significantly alter splicing isoform repertoires in cancer.
• Mutation-splicing relationships provide insights into oncogenic mechanisms.
• Findings support the development of precision medicine strategies targeting splicing alterations.