title: RAS signaling dysregulation in human embryonal Rhabdomyosarcoma.
abstract: Rhabdomyosarcoma (RMS) is a common childhood solid tumor, resulting from dysregulation of the skeletal myogenesis program. Two major histological subtypes occur in childhood RMS, embryonal and alveolar. While chromosomal rearrangements account for the majority of alveolar tumors, the genetic defects underlying the pathogenesis of embryonal RMS remain largely undetermined. A few studies performed on small series of embryonal tumors suggest that dysregulation of RAS function may be relevant to disease pathogenesis. To explore further the biological and clinical relevance of mutations with perturbing consequences on RAS signaling in embryonal RMS, we investigated the prevalence of PTPN11, HRAS, KRAS, NRAS, BRAF, MEK1, and MEK2 mutations in a relatively large cohort of primary tumors. While HRAS and KRAS were found to be rarely mutated, we identified somatic NRAS lesions in 20% of cases. All mutations were missense and affected codon 61, with the introduction of a positive charged amino acid residue representing the most common event. PTPN11 was found mutated in one tumor specimen, confirming that somatic defects in this gene are relatively uncommon in RMS, while no mutation was observed in BRAF and MEK genes. Although no clear association of mutations with any clinical variable was observed, comparison of the outcome between mutation-positive and mutation-negative cases indicated a trend for a higher percentage of patients exhibiting a better outcome in the former. Our findings provide evidence that dysregulation of RAS signaling is a major event contributing to embryonal RMS pathogenesis.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. simone.martinelli@iss.it
authors.forename: Simone
authors.initials: S
authors.lastname: Martinelli
authors.forename: Heather P
authors.initials: HP
authors.lastname: McDowell
authors.forename: Silvia Delle
authors.initials: SD
authors.lastname: Vigne
authors.forename: George
authors.initials: G
authors.lastname: Kokai
authors.forename: Stefania
authors.initials: S
authors.lastname: Uccini
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Carlo
authors.initials: C
authors.lastname: Dominici
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D018631:ras Proteins