Wilms Tumour

Paediatric Molecular Pathology Team

Section: Section of Paediatric Oncology

Wilms tumour (nephroblastoma) is the most common paediatric renal malignancy, affecting approximately 1 in 10,000 children before the age of 15 years. Most Wilms' tumours are of low stage, have a favourable histology, and with improved multimodality therapy the overall survival is high. Despite this, there remains a group of relapsing patients for whom intensive salvage regimens result in survival of only 50%. Genes involved in nephrogenesis, and particularly the mesenchymal to epithelial transition that accompanies the ingrowth of the ureteric bud into the metanephric blastema, have also been implicated in Wilms tumorigenesis, however to date there are no specific genes known to be involved in tumour relapse.

Work within our laboratory has been engaged in the use of microarray-based gene expression and copy number profiling of Wilms' tumours and their purported precursor lesions in order to identify novel molecular alterations associated with histological subtypes and treatment response.

Array CGH of favourable histology Wilms' tumours

Previous work in the Section of Paediatric Oncology (Professor Kathy Pritchard-Jones) using comparative genomic hybridisation (CGH) to metaphase chromosomes has highlighted an increased frequency of gain in DNA copy number on chromosome 1q in tumours which went on to relapse, with a relative risk of 4.5. We have been extending and refining this analysis by carrying out microarray-based comparative genomic hybridisation (array CGH) on a series of more than 100 Wilms tumour samples, enriched for cases which recurred, in order to identify changes in DNA copy number associated with clinical outcome. Validation by immunohistochemistry and chromogenic in situ hybridisation (CISH) on tissue microarrays has identified a number of promising candidate genes, which are being investigated for their functional significance in Wilms tumour model systems.

Molecular profiling of anaplastic Wilms tumour

Approximately 1 in 20 Wilms' tumours are associated with 'unfavourable' histology due to the presence of nuclear anaplasia, and overall survival of children with anaplastic Wilms tumour is as low as 50%. Although several studies have shown a high frequency of TP53 mutations in anaplastic Wilms tumour, few studies have identified other molecular changes associated with anaplasia, and high resolution molecular profiles have only been published for small numbers of tumours. We are carrying out array CGH and expression profiling of a large series of anaplastic Wilms' tumours in order to compare the molecular profiles favourable histology (FH) samples, with the aim of identifying both the common and distinguishing features of these histological subtypes.

Nephrogenic rests and their association with Wilms tumorigenesis

Nephrogenic rests are abnormally persistent foci of embryonal cells that are thought to be precursor lesions of Wilms tumour, as they are encountered in 25-40% of patients with nephroblastoma (up to 100% in bilateral disease), and in 1% of infant autopsies. In diffuse hyperplastic nephroblastomatosis, the risk for the development of Wilms tumour is extraordinarily high. We have initiated a project to determine the earliest genetic alterations in the development of Wilms tumour by the molecular profiling of nephrogenic rests. Using whole genome amplification methods to carry out array CGH profiling of microdissected formalin-fixed, paraffin embedded specimens, we have identified a number of alterations which are being confirmed by immunohistochemistry and CISH.