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

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticle

31 Citations (Scopus)

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”). A pan-cancer analysis by Kahles et al. shows increased alternative splicing events in tumors versus normal tissue and identifies trans-acting variants associated with alternative splicing events. Tumors contain neojunction-derived peptides absent in normal samples, including predicted MHC-I binders that are putative neoantigens.

Original languageEnglish (US)
Pages (from-to)211-224.e6
JournalCancer Cell
Volume34
Issue number2
DOIs
StatePublished - Aug 13 2018

Fingerprint

Alternative Splicing
Neoplasms
Exons
Exome
Peptides
Atlases
Major Histocompatibility Complex
Proteomics
Nucleotides
Genome
RNA
Breast Neoplasms

Keywords

  • alternative splicing
  • cancer
  • CPTAC
  • exome
  • GTEx
  • immunoediting
  • immunotherapy
  • MS proteomics
  • neoantigens
  • RNA-seq
  • splicing QTL
  • TCGA
  • TCGA Pan-Cancer Atlas
  • tumor-specific splicing

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. / The Cancer Genome Atlas Research Network.

In: Cancer Cell, Vol. 34, No. 2, 13.08.2018, p. 211-224.e6.

Research output: Contribution to journalArticle

The Cancer Genome Atlas Research Network. / Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. In: Cancer Cell. 2018 ; Vol. 34, No. 2. pp. 211-224.e6.
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