Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways

Cancer Cell. 2019 Mar 18;35(3):441-456.e8. doi: 10.1016/j.ccell.2019.02.002.


Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis. Using mathematical deconvolution strategies to unravel the complex copy-number profiles and mutational timing models we infer distinct evolutionary pathways of these rare cancers. In addition, 15% of tumors exhibited raised mutational burdens that correlated with gene expression signatures of immune infiltration, and good prognosis.

Keywords: cancer evolution; copy-number signatures; genomics; immuno-oncology; mutational signatures; sarcoma; tumor mutational burden.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Methylation*
  • Evolution, Molecular
  • Gene Duplication
  • Gene Expression Profiling / methods*
  • Humans
  • Mutation
  • Ploidies
  • Prognosis
  • Sarcoma / genetics*
  • Sequence Analysis, DNA / methods*