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

Kahles, André; Lehmann, Kjong-Van; Toussaint, Nora C; Hüser, Matthias; Stark, Stefan G; Sachsenberg, Timo; Stegle, Oliver; Kohlbacher, Oliver; Sander, Chris; Rätsch, Gunnar (2018). Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. Cancer cell, 34(2), 211-224.e6. Cell Press 10.1016/j.ccell.2018.07.001

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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").

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