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A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations

Nature Genetics volume 46, pages 595600 (2014) | Download Citation


Rhabdomyosarcoma, a cancer of skeletal muscle lineage, is the most common soft-tissue sarcoma in children1. Major subtypes of rhabdomyosarcoma include alveolar (ARMS) and embryonal (ERMS) tumors2,3. Whereas ARMS tumors typically contain translocations generating PAX3-FOXO1 or PAX7-FOXO1 fusions that block terminal myogenic differentiation4,5,6, no functionally comparable genetic event has been found in ERMS tumors. Here we report the discovery, through whole-exome sequencing, of a recurrent somatic mutation encoding p.Leu122Arg in the myogenic transcription factor MYOD1 in a distinct subset of ERMS tumors with poor outcomes that also often contain mutations altering PI3K-AKT pathway components. Previous mutagenesis studies had shown that MYOD1 with a p.Leu122Arg substitution can block wild-type MYOD1 function and bind to MYC consensus sequences7, suggesting a possible switch from differentiation to proliferation. Our functional data now confirm this prediction. Thus, MYOD1 p.Leu122Arg defines a subset of rhabdomyosarcomas eligible for high-risk protocols and the development of targeted therapeutics.

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We thank H. Hosoi (Kyoto Prefectural University of Medicine) and S. Tanaka and M. Tsuda (both at Hokkaido University) for providing cell lines. We also thank T. Akagi and K. Sasai (both at KAN Research Institute, Inc.) for providing the pcx4bleo plasmid. We are also grateful to J. Zhao for technical assistance with microarray analysis, to L. Borsu for assistance with Sequenom analyses and to E. de Stanchina and R. Tieu for the xenograft studies. This work was supported by a generous donation from M.B. Zuckerman (M.L.), by NIH P01 CA047179 (S.S.), by NCI P50 CA140146 (M.L., N.D.S. and S.S.), by a National Center for Research Resources (NCRR) Clinical Translational Science Center grant (M.P. and N.D.S.) and by the Virginia and Daniel K. Ludwig Trust for Cancer Research (J.A.F.). S.K. was supported in part by the Yasuda Medical Foundation and the HIROKO International Academic Exchange Foundation. F.G.B. is supported by the Intramural Research Program of the National Cancer Institute. The Memorial Sloan Kettering Cancer Center Sequenom facility was supported by the Anbinder Fund, and the Genomics and Bioinformatics Cores are supported by Cancer Center Core grant NCI P30 CA008748.

Author information

Author notes

    • Shinji Kohsaka
    • , Neerav Shukla
    •  & Nabahet Ameur

    These authors contributed equally to this work.


  1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Shinji Kohsaka
    • , Nabahet Ameur
    • , Tatsuo Ito
    • , Charlotte K Y Ng
    • , Lu Wang
    • , Diana Lim
    • , Angela Marchetti
    • , Snjezana Dogan
    • , Jorge S Reis-Filho
    •  & Marc Ladanyi
  2. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Shinji Kohsaka
    • , Nabahet Ameur
    •  & Marc Ladanyi
  3. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Neerav Shukla
    • , Paul Meyers
    •  & Leonard H Wexler
  4. Genomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Agnes Viale
  5. Bioinformatics Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Mono Pirun
    •  & Nicholas D Socci
  6. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Li-Xuan Qin
  7. Department of Pathology, University Hospital Gasthuisberg and University of Leuven, Leuven, Belgium.

    • Raf Sciot
  8. Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska, USA.

    • Julia Bridge
  9. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Samuel Singer
  10. Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.

    • Frederic G Barr
  11. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Jonathan A Fletcher


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S.K. performed myogenic differentiation studies, individual ChIP assays and in vivo studies. N.S. collected and analyzed clinical data and performed Sequenom genotyping studies with assistance from D.L. and A.M. N.A. obtained whole-exome and whole-transcriptome sequencing data with assistance from A.V., and M.P. and N.D.S. processed and analyzed the data. S.K. obtained expression microarray data with assistance from A.V., and L.-X.Q. analyzed the data. T.I. generated ChIP-seq data with assistance from A.V., and the data were processed by M.P. and N.D.S. and analyzed by C.K.Y.N. and J.S.R.-F. L.W. generated and interpreted the Affymetrix OncoScan array data. R.S., J.B., S.S., P.M., L.H.W., F.G.B., S.D. and J.A.F. provided rhabdomyosarcoma samples or cell lines, including clinical or pathological data. S.K., N.S. and M.L. drafted, edited and wrote the manuscript. M.L. led the project and manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Marc Ladanyi.

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    Complete lists of variant calls from next-generation sequencing.

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