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

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

来源：Nature Genetics, 2014, 46(6): 595-600.

DOI：10.1038/ng.2969

Rhabdomyosarcoma, a cancer of skeletal muscle lineage, is the most common soft-tissue sarcoma in children(1). Major subtypes of rhabdomyosarcoma include alveolar (ARMS) and embryonal (ERMS) tumors(2,3). Whereas ARMS tumors typically contain translocations generating PAX3-FOXO1 or PAX7-FOXO1 fusions that block terminal myogenic differentiation(4-6), 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 sequences(7), 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.

• 出版日期2014-6