Clonality and Evolutionary History of Rhabdomyosarcoma

Li Chen, Jack F. Shern, Jun S. Wei, Marielle E. Yohe, Young K. Song, Laura Hurd, Hongling Liao, Daniel Catchpoole, Stephen X. Skapek, Frederic G. Barr, Douglas S. Hawkins, Javed Khan

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. We discover several early mutations in non-RAS mutated samples and predict them to be drivers in PFN-RMS including recurrent mutation of PKN1. In contrast, we find that PAX-fusion-positive (PFP) subtype tumors have undergone whole-genome duplication in the late stage of cancer evolutionary history and have acquired fewer mutations and subclones than PFN-RMS. Moreover we predict that the PAX3-FOXO1 fusion event occurs earlier than the whole genome duplication. Our findings provide information critical to the understanding of tumorigenesis of RMS.

Original languageEnglish (US)
Article numbere1005075
JournalPLoS genetics
Issue number3
StatePublished - Mar 13 2015

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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