Journal Article

TP53 Mutational Status Is a Potential Marker for Risk Stratification in Wilms Tumour with Diffuse Anaplasia

Williams, Richard D., Sebire, Neil J., Pritchard-Jones, Kathy, Popov, Sergey D., Anderson, James R., Dome, Jeffrey S., Chagtai, Tasnim, Perlman, Elizabeth, Maschietto, Mariana, Vujanic, Gordan, Grundy, Paul

2014

Overview

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. 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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abnormalities / Anaplasia - genetics / Anaplasia - metabolism / Anaplasia - mortality / Bioindicators / Biological activity / Biology and Life Sciences / Biomarkers / Biomarkers, Tumor - genetics / Cancer / Cell cycle / Child / Child, Preschool / Children & youth / Childrens health / Confidence intervals / Copy number / Deoxyribonucleic acid / Deregulation / DNA / DNA Copy Number Variations / DNA Mutational Analysis / DNA repair / Frameshift Mutation / Gene expression / Genetic Association Studies / Genomes / Genomic Instability / Histology / Humans / Infant / Kidney - pathology / Kidney Neoplasms - genetics / Kidney Neoplasms - metabolism / Kidney Neoplasms - mortality / Medical prognosis / Medical research / Medicine and Health Sciences / Mutation / Neoplasm Recurrence, Local - genetics / Oncology / p53 Protein / Pathology / Patients / Polymorphism, Single Nucleotide / Prognosis / Proportional Hazards Models / Risk analysis / Risk Assessment / Stability / Transcriptome / Tumor Suppressor Protein p53 - genetics / Tumors / Wilms Tumor - genetics / Wilms Tumor - metabolism / Wilms Tumor - mortality