Abstract
PurposeThe 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.Patients and MethodsWe 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.ResultsFrom 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.ConclusionThis 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.
Highlights
Wilms tumour (WT) or nephroblastoma, the most frequent renal tumour of childhood, affects around 1 in 10,000 children before the age of 15 years
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
Due to the rarity of diffuse anaplasia in Wilms tumours (DAWT), samples were pooled from two major tumour banks (NWTSG-5 and UK SIOP 2001)
Summary
Wilms tumour (WT) or nephroblastoma, the most frequent renal tumour of childhood, affects around 1 in 10,000 children before the age of 15 years. Most patients with WT in the Western world are treated within prospective clinical trials conducted by either the International Society of Paediatric Oncology - Renal Tumor Study Group (SIOP-RTSG, Europe) or the Children’s. A substantial minority (,25%) respond poorly or relapse with current therapies and approximately 50% of these children will succumb to their tumour despite intensive re-treatment [9,10]. Risk stratification is largely based on tumour stage and histology which is key to improving clinical management; 4–10% of WT display anaplasia, which is defined morphologically by the presence of cells with at least threefold nuclear enlargement, hyperchromasia and abnormal mitotic figures [11]. Presence of DA is the most important adverse prognostic indicator in pre-treated (SIOP) and in chemotherapy-naıve tumours (COG) and patients are assigned to more intensive treatment [13,14]
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