Molecular Risk Groups in Wilms Tumour

Childhood Cancer Biology Team

Section: Section of Paediatric Oncology

Wilms tumour, or nephroblastoma, is a childhood cancer with a high cure rate. Approximately 90% of children can expect to be cured with current therapies. However, nearly half of children with Wilms tumour receive treatments with the potential for causing long-term damage to the heart muscle (doxorubicin) or to growth, fertility and increased risk of second tumours (radiotherapy). The current approach to risk stratification, which determines treatment intensity, uses tumour stage and histology. In the current UK clinical trial for treating Wilms tumour, a new histological risk classification has been introduced that has defined a new high risk subgroup of tumours where a large proportion of primitive blastemal cells survives pre-operative chemotherapy. However, this classification is somewhat subjective and tumours may fall into a ‘grey’ area where the exact cellular composition is not easy to define.

The aim of our research is to correlate comprehensive molecular profiles of Wilms tumour in relation to currently defined clinical and pathological risk groups and treatment outcome. We aim to define more robust markers of this new histological risk grouping and to identify the aberrant molecular pathways responsible for ‘high’ and ‘low’ risk tumour behaviour. Array CGH, expression profiling, LOH, and mutation screening, amongst other techniques, are being carried out, with particular focus on the molecular genetics underlying the chemoresistant blastemal type.

Although the underlying genetics of Wilms tumour development are still largely unknown, somatic mutations in the WT1 gene are present in approximately 15% of sporadic Wilms tumour cases. Of these 15%, it is reported that approximately half also harbour mutations in the beta catenin, which as well as playing a role on cell-cell adhesion through interactions with E-cadherin, is also a key player in the Wnt signalling pathway. We are screening a series of Wilms tumours for mutations not only in WT1 and beta catenin, but also other genes associated with beta catenin/Wnt signalling, in order to ascertain whether dysregulation on this pathway is a feature of all WT1 mutant tumours. In addition, we are also screening candidate genes at known Wilms tumour loci such as HRPT2 on 1q25 and ksp-cadherin on 16q22.

This work is done in close collaboration with Dr Chris Jones, Paediatric Molecular Pathology Team and the national paediatric Renal tumours pathology review panel (Dr Gordan Vujanic, Cardiff, Dr Anna Kelsey, Manchester, Dr Neil Sebire, Great Ormond Street Hospital) and the clinicians of the UK Children’s Cancer Study Group.