title: WTX mutations can occur both early and late in the pathogenesis of Wilms tumour.
abstract: BACKGROUND
  Somatic mutations in the X-linked tumour suppressor gene WTX have been observed in 6- 30% of sporadic cases of Wilms tumour. Germline mutations in the same gene cause the sclerosing skeletal dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS). No evidence points towards a susceptibility to the development of tumours in individuals with OSCS, suggesting that there are unrecognised additional determinants that influence the phenotypic outcome associated with germline mutations in WTX. One explanation may be that a somatic mutation in WTX may need to occur late in tumour development to contribute to tumourigenesis.
  
  
  METHODS
  Here a panel of four sporadic Wilms tumours with associated nephrogenic rest tissue and characterised WTX and CTNNB1 mutations is studied to ascertain the temporal sequence of acquisition of these mutations. Additionally, a family with OSCS is described segregating a germline mutation in WTX and manifesting a lethal phenotype in males. One male from this family had bilateral multifocal nephrogenic rests at autopsy.
  
  
  RESULTS
  In one of the four tumours the WTX mutation was present in both tumour and rest tissue indicating it had arisen early in tumour development. In the remaining three tumours, the WTX mutation was present in the tumour only indicating late acquisition of these mutations.
  
  
  CONCLUSIONS
  These data indicate that WTX mutations can arise both early and late in Wilms tumour development. WTX mutations may predispose to nephrogenic rest development rather than Wilms tumour per se.
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, PO Box 913 Dunedin, New Zealand.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukuzawa
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Holman
authors.forename: C W
authors.initials: CW
authors.lastname: Chow
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Reeve
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D001848:Bone Diseases, Developmental / Q000473:pathology; D004252:DNA Mutational Analysis; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010026:Osteosclerosis / Q000473:pathology; D010375:Pedigree; D012886:Skull / Q000002:abnormalities; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D025521:Tumor Suppressor Proteins