Recent Developments in the Molecular Pathology of Paediatric Renal Tumours

ABSTRACT

The renal tumours of childhood include different tumours with distinct clinical presentations and histological features. More than 50 syndromes have been associated with an increased risk of Wilms tumour (WT), but they are present in only ~5% of all children who develop WT. Some children with apparently sporadic WT have a constitutional genetic change that has predisposed them to their tumour. Detailed analysis of histological subtype may aid in their identification, particularly those with tumours showing prominent rhabdomyoblastic changes in association with intralobar nephrogenic rests. Recently, a group of predisposed individuals with constitutional epigenetic mutations affecting imprinting of the IGF2 locus on chromosome 11p15.5 has been discovered. Rhabdoid tumour of kidney is the only non-Wilms renal tumour of childhood with a recognised genetic predisposition.

Nephrogenic rests are regarded as precursors of WT. Intralobar nephrogenic rests are associated with mutations in the WT1 gene, whereas perilobar nephrogenic rests are associated with allele loss at 11p15. Loss of heterozygosity (LOH) and loss of imprinting (LOI) are associated with different histological subtypes of Wilms tumour: LOI of IGF2 is associated with PLNR-like Wilms tumours whereas LOH 11p and/or somatic WT1 mutation is associated with ILNR-like Wilms tumours, though these associations are not absolute. A recently discovered WT-X gene shows no histological subtype correlation.

The currently defined ‘high risk’ subgroups used for treatment decision making according to therapeutic approach (LOH 1p/16q for immediate nephrectomy cases, ‘blastemal type’ histology in tumours treated with pre-operative chemotherapy) are insufficiently specific or sensitive to predict the majority of relapses and new molecular insights are needed. Progress in the identification of biomarkers for risk stratification in Wilms tumour is reviewed.

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