title: Identification of somatic and germ-line DICER1 mutations in pleuropulmonary blastoma, cystic nephroma and rhabdomyosarcoma tumors within a DICER1 syndrome pedigree.
abstract: DICER1 syndrome is a pediatric cancer predisposition condition causing a variety of tumor types in children and young adults. In this report we studied a family with two relatives presenting a variety of neoplastic conditions at childhood.
  
  
  
  Germ-line mutation screening of the complete coding region of the DICER1 gene in genomic DNA from the proband was performed. The presence of somatic DICER1 mutation and further alterations in driver genes was investigated in genomic DNA obtained from available tumor samples.
  
  
  
  A nonsense germ-line mutation in DICER1 causing a truncated protein at the IIIb domain level was identified segregating within a family including two affected relatives who developed in one case cystic nephroma and pleuropulmonary blastoma, and rhabdomyosarcoma and multinodular goiter in the other. Additional in trans DICER1 missense somatic mutations in the IIIb DICER1 domain were found both in the cystic nephroma and in the rhabdomyosarcoma, suggesting that neoplasms in this family might arise from the unusual two-hit mechanism for DICER-derived tumorigenesis in which after the presence of a truncated constitutive protein, a neomorphic DICER1 activity is somatically adquired. Additional genetic alterations, such as TP53 mutations, were identified in the rhabdomyosarcoma.
  
  
  
  Besides DICER1 loss of standard activity, oncogenic cooperation of other genes, as mutated TP53, may involve developing higher grade tumors within this syndrome. Given the broad clinical spectrum that may arise, genetic counseling and close surveillance must be offered to all family members at risk of DICER1 syndrome.
authors.affiliation: Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), AGC Laboratorio de Medicina, Hospital Universitario Central de Asturias (HUCA), Oviedo, 33011, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Fernández-Martínez
authors.affiliation: Unidad de Oncología Pediátrica, AGC Pediatría, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Villegas
authors.affiliation: Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), AGC Laboratorio de Medicina, Hospital Universitario Central de Asturias (HUCA), Oviedo, 33011, Spain.
authors.forename: Íñigo
authors.initials: Í
authors.lastname: Santamaría
authors.affiliation: Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), AGC Laboratorio de Medicina, Hospital Universitario Central de Asturias (HUCA), Oviedo, 33011, Spain.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Pitiot
authors.affiliation: Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), AGC Laboratorio de Medicina, Hospital Universitario Central de Asturias (HUCA), Oviedo, 33011, Spain.
authors.forename: Marta G
authors.initials: MG
authors.lastname: Alvarado
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernández
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Torres
authors.affiliation: Unidad de Cáncer Familiar, Servicio de Oncología Médica, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Paredes
authors.affiliation: Unidad de Cáncer Familiar, Servicio de Oncología Médica, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Blay
authors.affiliation: Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), AGC Laboratorio de Medicina, Hospital Universitario Central de Asturias (HUCA), Oviedo, 33011, Spain. mbalbin@hca.es.
authors.forename: Milagros
authors.initials: M
authors.lastname: Balbín
mesh_terms: D002675:Child, Preschool; D018389:Codon, Nonsense; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000473:pathology; D018201:Nephroma, Mesoblastic / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D000072417:Protein Domains; D018202:Pulmonary Blastoma / Q000235:genetics* / Q000473:pathology; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D043244:Ribonuclease III / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: DICER1 mutations; DICER1 syndrome