A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations Journal Article
| Authors: | 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.; Fletcher, J. A.; Reis-Filho, J. S.; Ladanyi, M. |
| Article Title: | A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations |
| 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. © 2014 Nature America, Inc. |
| Keywords: | adolescent; adult; child; clinical article; preschool child; school child; young adult; sequence analysis; somatic mutation; protein function; protein binding; phosphatidylinositol 3 kinase; nucleotide sequence; mutagenesis; embryonal rhabdomyosarcoma; protein polymorphism; exome; human; male; female; priority journal; article; myod1 protein |
| Journal Title: | Nature Genetics |
| Volume: | 46 |
| Issue: | 6 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2014-06-01 |
| Start Page: | 595 |
| End Page: | 600 |
| Language: | English |
| DOI: | 10.1038/ng.2969 |
| PROVIDER: | scopus |
| PUBMED: | 24793135 |
| PMCID: | PMC4231202 |
| DOI/URL: | |
| Notes: | Nat. Genet. -- Export Date: 8 July 2014 -- CODEN: NGENE -- Molecular Sequence Numbers: GENBANK: GSE56078, GSE56079; -- Source: Scopus |
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