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Published on: December 9, 2016
Long-Read Sequencing Reveals Tumor-Specific Splicing Isoforms as Therapeutic Targets in Non-Small-Cell Lung Cancer
Yifei Li1, Liying Zhou2, Hexin Li1
1Clinical Biobank and.
Abstract:
Despite extensive transcriptomic alterations observed in tumors, the global landscape of isoform-level alternative splicing in cancer remains largely unexplored. Leveraging long-read sequencing, we successfully identified and characterized full-length isoforms, together with tumor-specific splicing events in non-small-cell lung cancer (NSCLC). Our analysis identified 38,058 previously unannotated isoforms, which were subsequently validated using orthogonal multiomics datasets to confirm their transcriptional and translational activities. Notably, 269 splicing events were characterized as tumor specific, with 17 showing significant associations with NSCLC subtypes, while 13 were enriched across all NSCLC cases. Among these events, skipped exons in IFI27, PUF60, and ANAPC11, as well as an alternative first exon in YBEY, were absent from GENCODE annotations. These findings underscore the intricate complexity of isoforms and their clinical significance, particularly in terms of NSCLC subtype specificity and their potential as therapeutic targets. In conclusion, this study provides a valuable resource for the discovery of tumor-specific splicing targets in NSCLC, leveraging the unique advantages of long-read sequencing.
Insights
Long-read sequencing reveals novel, tumor-specific splicing events in non-small cell lung cancer (NSCLC). This study identifies previously unannotated isoforms and highlights their potential as diagnostic and therapeutic targets.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Alternative splicing significantly impacts cancer development but remains underexplored at the isoform level.
- Transcriptomic alterations are common in tumors, yet the full spectrum of splicing variations is not well understood.
Purpose of the Study:
- To identify and characterize full-length isoforms and tumor-specific splicing events in non-small cell lung cancer (NSCLC) using long-read sequencing.
- To validate the transcriptional and translational activity of novel isoforms.
- To explore the clinical significance of these splicing events in NSCLC subtypes.
Main Methods:
- Utilized long-read sequencing to identify and characterize full-length isoforms in NSCLC.
- Employed orthogonal multi-omics datasets for validation of isoform activity.
- Analyzed splicing events for tumor specificity and association with NSCLC subtypes.
Main Results:
- Identified 38,058 previously unannotated isoforms, confirming their transcriptional and translational activity.
- Characterized 269 tumor-specific splicing events, with 17 linked to NSCLC subtypes and 13 enriched across all cases.
- Discovered novel splicing events, including skipped exons in IFI27, PUF60, ANAPC11, and an alternative first exon in YBEY, not present in current annotations.
Conclusions:
- This study provides a comprehensive resource for understanding isoform complexity and tumor-specific splicing in NSCLC.
- Identified novel splicing events with potential clinical significance and as therapeutic targets.
- Highlights the power of long-read sequencing in uncovering previously hidden aspects of cancer biology.
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