Abstract 3829: TP53 mutation status defines two distinct classes of diffuse anaplastic Wilms tumor.

Abstract Wilms tumor (WT) is a paediatric renal tumor with a relapse rate of 10 to 15%. Tumor stage and the histological presence of diffuse anaplasia (DA) are the most important adverse prognostic factors in WT. Previous studies have described TP53 mutations at a frequency of up to 75% in DA WT cases, however only small cohorts were analysed. The aim of this study was to evaluate the frequency of TP53 mutations in a large group of DA WT and correlate these data with tumor and patient characteristics. DA WTs from 61 patients were analysed for TP53 mutations using Sanger sequencing. A paediatric pathologist confirmed the presence of anaplastic cells in the specimen used for DNA extraction. Sequence alterations were classified as damaging or neutral mutations with reference to databases of known mutations and functional prediction algorithms (SIFT, PolyPhen2). Loss of 17p, where TP53 is located, was evaluated using CGH or SNP arrays and gene expression profiling was carried out using cDNA microarrays. Kaplan-Meier Survival analysis and Breslow's test were used to compare TP53 alterations with clinico-pathological characteristics. Of the 61 cases, 29 (47.5%) had at least one damaging TP53 mutation and 26 of these also had TP53 loss. Most of the cases (20 out of 29, 68.9%) presented TP53 mutations located within exons 5 to 8. These exons comprise the DNA-binding domain where the hotspots are located. The other 32 DA WT cases did not harbour mutations but six had 17p loss. Patients with DA WT that carry TP53 mutations and/or 17p loss had a worse response to treatment than those patients that had wild type TP53 (p<0.01). The CGH profiles showed an increase in the number of gains and losses seen in DA WT with TP53 mutations, compared to those without, suggesting a more unstable genome. Gene expression profiling revealed 71 differentially expressed genes between DA WT with and without mutations. These genes may be associated with the anaplastic phenotype, but their role in the pathogenesis of WT remains to be confirmed. Evaluating a large series of anaplastic WT, we found that the frequency of TP53 mutations in DA WT was lower than previously reported. However, samples with apparent wild type TP53 will be further evaluated by deep-sequencing to determine if mutations are present in a minority cell population. The relatively high frequency of wild type TP53 in DA WT suggests that TP53 mutations are neither necessary nor sufficient to generate anaplasia. Grants: Cancer Research UK; EU FP7 P-medicine, Sophie Barringer Trust and GOSHCC. Citation Format: Mariana Maschietto, Tasnim Chagtai, Sergey D. Popov, Neil Sebire, Gordan Vujanic, Sandra Hing, Paul Grundy, Jeffrey S. Dome, Kathy Pritchard-Jones, Richard D. Williams. TP53 mutation status defines two distinct classes of diffuse anaplastic Wilms tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3829. doi:10.1158/1538-7445.AM2013-3829

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