Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients

By A. Kahles, Kjong-Van Lehmann, Nora C. Toussaint, Matthias Hüser, Stefan G. Stark, Timo T. Sachsenberg, Oliver Stegle, Oliver Kohlbacher, Christopher Sander, Gunnar Rätsch and 724 more. Cancer Cell, 2018

792 citations recorded by the source corpus.

SUMMARY Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions (“neojunctions”) in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders (“putative neoantigens”).

Subfields: Cancer Research, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/86ce86e249a1579f3d728e16420cdd2b2d7c2831

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Citations in the corpus

A systematic benchmark of Nanopore long read RNA sequencing for transcript level analysis in human cell lines (2021, background): “(6) Full-length reads enable the analysis of individual isoform expression The ability of long reads to unambiguously identify isoforms that are expressed enables the analysis of complex splicing events involving multiple exons.”
Genomic basis for RNA alterations in cancer (2020, result): “Consistent with previous findings using exome sequencing 33,34 , most mutations overlapping the essential dinucleotide motifs of the acceptor or donor site are associated with a splicing change—61% or 57%, respectively (Fig.”
Neoantigens: promising targets for cancer therapy (2023, background): “The highly aberrant splicing events in tumors expand the scope of tumor-specific neoantigens, especially in tumors with low rates of copy number variation and somatic mutations.(23,117,120)”
Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution. (2019, background): “Derepression of cryptic splice sites in human diseases can be caused either by mutations in cisacting silencing elements or deregulation of trans-acting repressors (Kahles et al., 2018; Ling et al., 2015; Sibley et al., 2016; Zarnack et al., 2013).”