title: Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies.
abstract: PTPN11 has been identified as a causative gene in Noonan syndrome (NS), responsible for about 50% of cases of NS. Given the association between NS and an increased risk of some malignancies, notably leukemia and probably some solid tumors including neuroblastoma (NB) and rhabdomyosarcoma (RMS), recent studies have reported that gain-of-function somatic mutations in PTPN11 occur in some hematological malignancies, especially de novo juvenile myelomonocytic leukemia (JMML) and in some solid tumors such as NB, although at a low frequency. In a screen for mutations of PTPN11 in 7 cell lines and 30 fresh tumors of RMS and in 25 cell lines and 40 fresh tumors of NB, we identified a missense mutation (A72T) in an embryonal RMS patient. In the RMS samples, we also detected mutations of NRAS in 1 cell line and 1 patient; both mutations were in embryonal RMSs and had no PTPN11 mutations. No mutations of PTPN11 were detected in NB. In 95 leukemia cell lines and 261 fresh leukemia samples including 22 JMMLs, 9 kinds of missense mutations were detected in 17 leukemia samples, which included 11 (50.0%) mutations in JMML samples and lower frequencies in other hematological malignancies. Furthermore, we identified 4 (18.2%) NRAS mutations and 1 (4.5%) KRAS mutation in 5 JMML samples, 1 of which had a concomitant PTPN11 mutation. Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Chen
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Hiwatari
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hanada
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Teruaki
authors.initials: T
authors.lastname: Hongo
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taki
authors.forename: Mizuho
authors.initials: M
authors.lastname: Ogasawara
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D018631:ras Proteins