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 journalArticle

25 Citations (Scopus)

Abstract

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
Volume11
Issue number3
DOIs
StatePublished - Mar 13 2015

Fingerprint

Rhabdomyosarcoma
mutation
Mutation
genome
Genome
history
tumor
neoplasms
History
Neoplasms
Loss of Heterozygosity
heterozygosity
carcinogenesis
cancer
germ cells
Carcinogenesis
gene
Genes
genes
sampling

ASJC Scopus subject areas

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

Cite this

Chen, L., Shern, J. F., Wei, J. S., Yohe, M. E., Song, Y. K., Hurd, L., ... Khan, J. (2015). Clonality and Evolutionary History of Rhabdomyosarcoma. PLoS Genetics, 11(3), [e1005075]. https://doi.org/10.1371/journal.pgen.1005075

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

In: PLoS Genetics, Vol. 11, No. 3, e1005075, 13.03.2015.

Research output: Contribution to journalArticle

Chen, L, Shern, JF, Wei, JS, Yohe, ME, Song, YK, Hurd, L, Liao, H, Catchpoole, D, Skapek, SX, Barr, FG, Hawkins, DS & Khan, J 2015, 'Clonality and Evolutionary History of Rhabdomyosarcoma', PLoS Genetics, vol. 11, no. 3, e1005075. https://doi.org/10.1371/journal.pgen.1005075
Chen L, Shern JF, Wei JS, Yohe ME, Song YK, Hurd L et al. Clonality and Evolutionary History of Rhabdomyosarcoma. PLoS Genetics. 2015 Mar 13;11(3). e1005075. https://doi.org/10.1371/journal.pgen.1005075
Chen, Li ; Shern, Jack F. ; Wei, Jun S. ; Yohe, Marielle E. ; Song, Young K. ; Hurd, Laura ; Liao, Hongling ; Catchpoole, Daniel ; Skapek, Stephen X. ; Barr, Frederic G. ; Hawkins, Douglas S. ; Khan, Javed. / Clonality and Evolutionary History of Rhabdomyosarcoma. In: PLoS Genetics. 2015 ; Vol. 11, No. 3.
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