Undifferentiated sarcomas (USARC) of adults are diverse, rare and aggressive soft tissue cancers. Recent efforts have confirmed that USARC exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the genomic basis of this structural complexity by integrating whole genome sequencing, ploidy analysis and methylation profiling of 53 USARC. We identified whole genome doubling as a prevalent and pernicious force in USARC tumourigenesis. Deconvolution of the complex copy number and rearrangement landscapes show distinct signatures associated with chromothripsis, early-haploidy, and successive whole-genome-doubling events, suggesting four divergent models of sarcoma development. We show similar distinct evolutionary tumourigenic pathways in different sarcoma subtypes from the Cancer Genome Atlas. Thirteen percent of tumours exhibited a hypermutator phenotype, opening new avenues for clinical management such as immunotherapy, whilst the period prior to and between genome doubling events may represent clinically relevant interventional points in USARC.
Steele, Christopher D. and Tarabichi, Maxime and Alexandrov, Ludmil B. and Oukrif, Dahmane and Ye, Hongtao and Fittall, Matthew and Lombard, Patrick and Martincorena, Inigo and Tarpey, Patrick S. and Collord, Grace and Strauss, Sandra J. and Berisha, Fitim and Jansen, Marnix and Behjati, Sam and Amary, M Fernanda and Tirabosco, Roberto and Campbell, Peter J. and Van Loo, Peter and Flanagan, Adrienne M. and Pillay, Nischalan, Undifferentiated Sarcomas Develop Through Distinct Evolutionary Pathways (2018). Available at SSRN: https://ssrn.com/abstract=3204559 or http://dx.doi.org/10.2139/ssrn.3204559
This version of the paper has not been formally peer reviewed.