Identification of candidate neoantigens produced by fusion transcripts in human osteosarcomas

Sci Rep. 2019 Jan 23;9(1):358. doi: 10.1038/s41598-018-36840-z.

Abstract

Osteosarcomas are characterized by highly disrupted genomes. Although osteosarcomas lack common fusions, we find evidence of many tumour specific gene-gene fusion transcripts, likely due to chromosomal rearrangements and expression of transcription-induced chimeras. Most of the fusions result in out-of-frame transcripts, potentially capable of producing long novel protein sequences and a plethora of neoantigens. To identify fusions, we explored RNA-sequencing data to obtain detailed knowledge of transcribed fusions, by creating a novel program to compare fusions identified by deFuse to de novo transcripts generated by Trinity. This allowed us to confirm the deFuse results and identify unusual splicing patterns associated with fusion events. Using various existing tools combined with this custom program, we developed a pipeline for the identification of fusion transcripts applicable as targets for immunotherapy. In addition to identifying candidate neoantigens associated with fusions, we were able to use the pipeline to establish a method for measuring the frequency of fusion events, which correlated to patient outcome, as well as highlight some similarities between canine and human osteosarcomas. The results of this study of osteosarcomas underscores the numerous benefits associated with conducting a thorough analysis of fusion events within cancer samples.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / immunology*
  • Antiporters / genetics
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / immunology*
  • Bone Neoplasms / pathology
  • CD8-Positive T-Lymphocytes / metabolism
  • CLOCK Proteins / genetics
  • Cation Transport Proteins / genetics
  • Cell Line, Tumor
  • Computational Biology / methods
  • Epitopes / genetics
  • Epitopes / immunology
  • Gene Expression Profiling
  • Genetic Loci
  • Genomic Instability
  • High-Throughput Nucleotide Sequencing
  • Mice
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / immunology*
  • Open Reading Frames
  • Osteosarcoma / genetics*
  • Osteosarcoma / immunology*
  • Osteosarcoma / pathology
  • Transcription, Genetic
  • Transcriptome

Substances

  • Antigens, Neoplasm
  • Antiporters
  • Cation Transport Proteins
  • Epitopes
  • Oncogene Proteins, Fusion
  • TMEM165 protein, mouse
  • CLOCK Proteins
  • CLOCK protein, human