title: Constitutional WT1 mutations in Wilms' tumor patients.
abstract: OBJECTIVE
  Patients with Wilms' tumors (WT) who carry constitutional mutations in the WT1 gene have been described in case reports and small case series. We sought to determine the frequency of constitutional WT1 mutations in a larger cohort, and to identify clinical manifestations associated with the risk for carrying a WT1 mutation.
  
  
  METHODS
  We collected clinical data and blood samples from 201 patients with a history of WT. Southern blot analysis, single-strand conformation polymorphism (SSCP) analysis, and direct DNA sequencing were performed on DNA isolated from peripheral-blood lymphocytes from each patient. Odds ratios (ORs) for the carriage of a germline mutation of the WT1 gene were calculated for patients who had specific clinical risk factors compared with those who did not.
  
  
  RESULTS
  Of 201 patients with WT in the cohort, eight patients were carriers of mutations in the WT1 gene. Six of the eight mutations were protein-truncating nonsense mutations. None of 56 patients with isolated unilateral WT was a carrier. The OR of carrying a WT1 mutation was elevated for patients with genitourinary anomalies (OR19.3; P < .002). Seven of 28 boys with WT with cryptorchidism carried WT1 mutations. No increased risk was observed for patients with nephrogenic rests, bilateral tumors, history of secondary cancers, or family history of WT.
  
  
  CONCLUSIONS
  Germline WT1 mutations in patients with WT are associated with genitourinary anomalies, especially cryptorchidism and/or hypospadias. Patients with WT and no genitourinary anomalies are at low risk for carrying a WT1 mutation. Constitutional WT1 mutations that encode truncated WT1 proteins may predispose to the development of cryptorchidism, hypospadias, and WTs.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115, USA. lisa_diller@dfci.harvard.edu
authors.forename: L
authors.initials: L
authors.lastname: Diller
authors.forename: M
authors.initials: M
authors.lastname: Ghahremani
authors.forename: J
authors.initials: J
authors.lastname: Morgan
authors.forename: P
authors.initials: P
authors.lastname: Grundy
authors.forename: C
authors.initials: C
authors.lastname: Reeves
authors.forename: N
authors.initials: N
authors.lastname: Breslow
authors.forename: D
authors.initials: D
authors.lastname: Green
authors.forename: D
authors.initials: D
authors.lastname: Neuberg
authors.forename: J
authors.initials: J
authors.lastname: Pelletier
authors.forename: F P
authors.initials: FP
authors.lastname: Li
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D016017:Odds Ratio; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*; D014564:Urogenital Abnormalities / Q000150:complications; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; D025721:WT1 Proteins