title: TP53 mutational status is a potential marker for risk stratification in Wilms tumour with diffuse anaplasia.
abstract: OBJECTIVE
  The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information.
  
  
  METHODS
  We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling.
  
  
  RESULTS
  From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes.
  
  
  CONCLUSIONS
  This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.
authors.affiliation: Cancer Section, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Mariana
authors.initials: M
authors.lastname: Maschietto
authors.affiliation: Cancer Section, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Williams
authors.affiliation: Cancer Section, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Tasnim
authors.initials: T
authors.lastname: Chagtai
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, United Kingdom.
authors.forename: Sergey D
authors.initials: SD
authors.lastname: Popov
authors.affiliation: Departments of Histopathology, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.affiliation: Department of Pathology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Gordan
authors.initials: G
authors.lastname: Vujanic
authors.affiliation: Department of Pathology, Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Perlman
authors.affiliation: Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Anderson
authors.affiliation: Departments of Pediatrics and of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Grundy
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's National Medical Center, Washington, District of Columbia, United States of America.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Dome
authors.affiliation: Cancer Section, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
mesh_terms: D000708:Anaplasia / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D042822:Genomic Instability; D006801:Humans; D007223:Infant; D007668:Kidney / Q000473:pathology*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000401:mortality
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53