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

TLDR

We reanalyzed RNA and whole‑exome sequencing from 8,705 TCGA patients across 32 cancer types to detect alternative splicing events and tumor‑specific variants. Tumors show up to 30% more alternative splicing events than normal tissue, harbor thousands of tumor‑specific neojunctions (≈930 per tumor on average), and contain additional trans‑acting variants (e.g., TADA1, PPP2R1A); breast and ovarian samples also yield ~1.7 neojunction‑derived and ~0.6 SNV‑derived peptides per tumor that bind MHC‑I.

Abstract

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").