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.
authors.affiliation: 1] Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [3].
authors.forename: Shinji
authors.initials: S
authors.lastname: Kohsaka
authors.affiliation: 1] Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2].
authors.forename: Neerav
authors.initials: N
authors.lastname: Shukla
authors.affiliation: 1] Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [3].
authors.forename: Nabahet
authors.initials: N
authors.lastname: Ameur
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Marchetti
authors.affiliation: Genomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Bioinformatics Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Mono
authors.initials: M
authors.lastname: Pirun
authors.affiliation: Bioinformatics Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.affiliation: Department of Pathology, University Hospital Gasthuisberg and University of Leuven, Leuven, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.affiliation: Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Bridge
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Meyers
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Wexler
authors.affiliation: Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Frederic G
authors.initials: FG
authors.lastname: Barr
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Dogan
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: 1] Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D002648:Child; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D017570:MyoD Protein / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D059467:Transcriptome; D055815:Young Adult
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt