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

Shinji Kohsaka, Neerav Shukla, Nabahet Ameur, Tatsuo Ito, Charlotte K.Y. Ng, Lu Wang, Diana Lim, Angela Marchetti, Agnes Viale, Mono Pirun, Nicholas D. Socci, Li Xuan Qin, Raf Sciot, Julia Bridge, Samuel Singer, Paul Meyers, Leonard H. Wexler, Frederic G. Barr, Snjezana Dogan, Jonathan A. FletcherJorge S. Reis-Filho, Marc Ladanyi

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Rhabdomyosarcoma, a cancer of skeletal muscle lineage, is the most common soft-tissue sarcoma in children. Major subtypes of rhabdomyosarcoma include alveolar (ARMS) and embryonal (ERMS) tumors. Whereas ARMS tumors typically contain translocations generating PAX3-FOXO1 or PAX7-FOXO1 fusions that block terminal myogenic differentiation, 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 sequences, 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.

Original languageEnglish
Pages (from-to)595-600
Number of pages6
JournalNature Genetics
Volume46
Issue number6
DOIs
Publication statusPublished - Jun 2014

ASJC Scopus subject areas

  • Genetics

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    Kohsaka, S., Shukla, N., Ameur, N., Ito, T., Ng, C. K. Y., Wang, L., Lim, D., Marchetti, A., Viale, A., Pirun, M., Socci, N. D., Qin, L. X., Sciot, R., Bridge, J., Singer, S., Meyers, P., Wexler, L. H., Barr, F. G., Dogan, S., ... Ladanyi, M. (2014). A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nature Genetics, 46(6), 595-600. https://doi.org/10.1038/ng.2969