Alternative mRNA splicing in cancer immunotherapy

Frankiw, Luke; Baltimore, David; Li, Guideng

doi:10.1038/s41577-019-0195-7

Cited by 185 publications

(179 citation statements)

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“…We ranked transcript abundance for each gene that had multiple isoforms and obtained the alternative splicing events from the most expressed transcript and the second most expressed transcript. We used a common model to classify the splicing events 56 , where alternative 5/3' splice site includes alternative promoter and alternative polyadenylation. Transcripts with more than one splicing event were classified as complex splicing changes ( Figure 2G).…”

Section: Comparison Of Flames To Other Toolsmentioning

confidence: 99%

Comprehensive characterization of single cell full-length isoforms in human and mouse with long-read sequencing

Tian

Jabbari

Thijssen

et al. 2020

Preprint

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Alternative splicing shapes the phenotype of cells in development and disease. Long-read RNA-sequencing recovers full-length transcripts but has limited throughput at the single-cell level. Here we developed single-cell full-length transcript sequencing by sampling (FLT-seq), together with the computational pipeline FLAMES to overcome these issues and perform isoform discovery and quantification, splicing analysis and mutation detection in single cells. With FLT-seq and FLAMES, we performed the first comprehensive characterization of the full-length isoform landscape in single cells of different types and species and identified thousands of unannotated isoforms. We found conserved functional modules that were enriched for alternative transcript usage in different cell populations, including ribosome biogenesis and mRNA splicing. Analysis at the transcript-level allowed data integration with scATAC-seq on individual promoters, improved correlation with protein expression data and linked mutations known to confer drug resistance to transcriptome heterogeneity. Our methods reveal previously unseen isoform complexity and provide a better framework for multi-omics data integration.

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Section: Comparison Of Flames To Other Toolsmentioning

confidence: 99%

Comprehensive characterization of single cell full-length isoforms in human and mouse with long-read sequencing

Tian

Jabbari

Thijssen

et al. 2020

Preprint

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“…Moreover, FDA granted accelerated approval to the combination of checkpoint inhibitors and the VEGFR inhibitor lenvatinib for the treatment of patients with advanced endometrial cancer with disease progression following prior systemic therapy (58). Several studies have shown that peptides derived from altered mRNA splicing in tumors could bind to MHC class I molecules representing tumor-specific mRNA splicing derived neoantigens (59). Notably, inhibition of SRPK1 induced > 1600 mis-spliced events in Figure S1: Designing a s-SILAC kinase standard for measuring kinase abundance in tissues.…”

Section: Discussionmentioning

confidence: 99%

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

Johnson

Kumar

Kurimchak

et al. 2020

Preprint

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Protein kinases (collectively, termed the kinome) represent one of the most tractable drug targets in the pursuit of new and effective cancer treatments. However, less than 20% of the kinome is currently being explored as primary targets for cancer therapy, leaving the majority of the kinome untargeted for drug therapy. Chemical proteomics approaches such as Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS) have been developed that measure the

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“…Previous work has suggested that splicing dysregulation in cancer may be a greater source of tumor specific antigens than somatic point mutations [3,25]. Application of the Bisbee outlier test to cancer patient samples may enable the discovery of tumor-specific splicingderived neoantigens, which could be therapeutic or vaccine targets.…”

Section: Discussionmentioning

confidence: 99%

“…This outlier analysis may be useful to identify disruption of splicing due to somatic mutations or expression of known tumor specific splice isoforms in an individual's tumor [22,23]. Outlier analysis may also be used to identify splice variant-induced antigens in a target individual's tumor that do not exist in normal tissues [3,[23][24][25]. In addition, some rare Mendelian disorders are caused by variants that disrupt splicing.…”

Section: Introductionmentioning

confidence: 99%

“…For example, an alternate splice site in the BCL2L1 gene gives rise to different protein isoforms that have opposing effects on apoptosis [27]. Alternative splicing may also give rise to novel protein sequences in a cancer cell that could be recognized by the immune system [3,[23][24][25]. In this light, genomics, transcriptomics, and proteomics are being used together more often in an effort to more fully characterize phenotypic effects resulting from genomic alterations and pathway dysregulation [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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Bisbee: A proteomics validated analysis package for detecting differential splicing, identifying splice outliers, and predicting splice event protein effects

Halperin

Hegde

Lang

et al. 2020

Preprint

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Here we present a novel statistical approach to splicing outlier and differential splicing detection, implemented in a software package called Bisbee. We leverage Bisbee's prediction of protein level effects to benchmark using matched RNAseq and mass spectrometry data from normal tissues. Bisbee exhibits improved sensitivity and specificity over existing approaches. We applied Bisbee to confirm a pathogenic splicing event in a rare disease and to identify tumor-specific splice isoforms associated with an oncogenic splice factor mutation. We also identified common tumor associated splice isoforms replicated in an independent dataset, demonstrating the utility of Bisbee in discovering disease relevant splice variants.

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Alternative mRNA splicing in cancer immunotherapy

Cited by 185 publications

References 185 publications

Comprehensive characterization of single cell full-length isoforms in human and mouse with long-read sequencing

Comprehensive characterization of single cell full-length isoforms in human and mouse with long-read sequencing

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

Bisbee: A proteomics validated analysis package for detecting differential splicing, identifying splice outliers, and predicting splice event protein effects

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