Wilms Tumor: Towards integration of histopathological and genomic characteristics

Wilms Tumor (WT) is the most common pediatric renal tumor, accounting for ~90% of cases. Postoperative treatment stratification of WTs is mainly based on histological subclassification of the surgical specimen. High-risk WTs have poor outcome and are therefore stratified towards more intensive treatment regimens. Still, in Europe, the absolute number of relapses remains highest in the intermediate-risk group. Furthermore, intensified therapeutic regimens result in high percentages of direct and late side-effects. This underlines the need to identify relevant (molecular) characteristics for improvement of risk group stratification and development of targeted treatment approaches. The general objectives were to optimize current European pathology guidelines for pediatric renal tumors, and to contribute to further integration of histopathology and genetics by unravelling the molecular characteristics of WTs, by identifying new candidate biomarkers and potential treatment targets.

On behalf of the International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG), internationally harmonized pathology guidelines (supporting the UMBRELLA protocol) were designed for optimal tissue sampling for diagnostic and research goals as well as to establish (inter)national high-quality data- and biobanks. Still, despite adequate sampling, making a final diagnosis can be difficult due to high inter- and intratumor-heterogeneity. Therefore, we also provided a review on the differential diagnosis of pediatric renal tumors, by using a histological pattern-based approach.

To further unravel the genetic background of WTs, to identify new therapeutic targets, and in search of novel prognostic biomarkers for improvement of treatment stratification, we collaborated within the US-based TARGET project (Therapeutically Applicable Research to Generate Effective Treatments project) of the Children’s Oncology Group. This project included a comprehensive molecular characterization of a large number of high-risk pediatric renal tumors using a variety of genome-wide sequencing and array-based methods. We identified recurrent somatic mutations in many genes, several (e.g. SIX1/2) not previously associated to WT development, as well as new germline mutations. Somatic mutations co-occurring in SIX1/2 and DROSHA conferred a worse prognosis, and this combination of mutations might thus be a new biomarker. The TARGET project also showed that TP53 mutations are the key regulators in the development of anaplasia, and that the presence of TP53 loss is of prognostic significance in stage III/IV WTs, indicating that TP53 loss might be a valuable prognostic marker in anaplastic WTs.

Overall, the TARGET study increased our understanding of the genomic landscape of WTs, and, by now, over 50 candidate driver genes are known. However, converging all data showed that, in general, only two pivotal pathways are disrupted: early nephrogenesis and epigenetic regulation of transcription, providing possible therapeutic strategies.

To validate the role of newly identified recurrently mutated genes, possible biomarkers and therapeutic targets, research models for pediatric renal tumors are necessary. However, there is an evident lack of adequate representative and reliable models. Nevertheless, the relatively new organoid technology is a promising tool, with a high success rate of establishment for studying tumorigenesis, biobanking of tumor-derived patient material, and for drug screening. Hence, organoids may help to close the gap between cell lines/animal models and clinical trials.