Grundy, Richard Guy; (1997) The Molecular Genetics of Wilms Tumour And The Wilms Tumour Predisposition Syndromes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A molecular genetic analysis of Wilms tumour and the Wilms tumour predisposition syndromes. Genetic analysis of Wilms tumour (WT) and WT predisposition syndromes has revealed that a complex set of genetic events are associated with the development of this tumour. This thesis analyses specific genetic loci in a series of patients and tumours in order to gain a greater understanding of the molecular aetiology of this tumour. Sporadic Wilms tumours are the most common type and constitute the bulk of the analysis presented. The WT1 gene in 11p13 was analysed using SSCP and DNA sequencing in 36 tumours. Mutations were only found in 1 of 32 sporadic Wilms tumours, strongly suggesting that WT1 has only a limited role to play in the development of sporadic WT. Karyotypic analysis and Loss of Heterozygosity (LOH) studies have implicated loci on chromosome arms 7p and 16q in Wilms tumourigenesis. Paired constitutional and tumour DNA from sporadic WT were studied for LOH using polymorphic microsatellite repeats from both these chromosomes. 15% showed LOH for 16q and there was evidence for a worse outcome in this small group. LOH for 7p was found in 10% of cases and in one tumour a homozygous deletion was detected, this finding suggests the locaton of a tumour suppressor gene on 7p. Previous analysis of Beckwith-Wiedemann syndrome (BWS) patients has suggested another WT predisposition gene lies in 11p15. Two patients with constitutional translocations were analysed using fluoresence in situ hybridisation (FISH) and trisomy for the 11p15 region was identified. Analysis of the extent of the triplication was studied using 11p15-specific cosmids. The importance of these observations in the development of WT are discussed. Perlman syndrome (PS) is another WT predisposition syndrome and cytogenetic analysis in two patients with this syndrome suggested rearrangements of 11p15. Detailed FISH and molecular analysis has been used to characterise the nature of these rearrangments. The data presented in this thesis adds to the body of evidence demonstrating the complex nature of the molecular mechanisms underlying Wilms tumorigenesis.

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