title: Noonan syndrome, the SOS1 gene and embryonal rhabdomyosarcoma.
abstract: Noonan Syndrome (NS) is an autosomal dominant condition characterized by short stature, facial dysmorphisms, and congenital heart defects, and is caused by mutations in either PTPN11, KRAS, NRAS, SHOC2, RAF1, or SOS1. Furthermore, NS is known for its predisposition to develop cancer, particularly hematological malignancies and specific solid tumors, mainly neuroblastoma and embryonal rhabdomyosacroma (ERMS). Until recently, however, cancer predisposition in NS patients with SOS1 mutations was not reported. Here we present a NS patient with a de novo germline SOS1 mutation (p.Lys728Ile) and ERMS. This heterozygous germline mutation was homozygously present in the ERMS of this patient due to an acquired uniparental disomy (UPD) of chromosome 2. In addition, several other chromosomal aberrations were encountered, some of which are known to recurrently occur in ERMS. Sequence analysis of the SOS1 gene in 20 sporadic ERMS tumors failed to reveal any pathogenic mutations, implicating that SOS1 is not a major player in the development of this tumor outside the context of NS.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.jongmans@antrg.umcn.nl
authors.forename: Marjolijn C J
authors.initials: MC
authors.lastname: Jongmans
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.forename: Linda
authors.initials: L
authors.lastname: Hilkens
authors.forename: Uta
authors.initials: U
authors.lastname: Flucke
authors.forename: Ineke
authors.initials: I
authors.lastname: van der Burgt
authors.forename: Kees
authors.initials: K
authors.lastname: Noordam
authors.forename: Martina
authors.initials: M
authors.lastname: Ruiterkamp-Versteeg
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.forename: Willy M
authors.initials: WM
authors.lastname: Nillesen
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
mesh_terms: D011905:Genes, ras; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000235:genetics; D019337:Hematologic Neoplasms / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D009634:Noonan Syndrome / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics*; D024182:Uniparental Disomy
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C112913:SHOC2 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11