Normal cellular homeostasis is established and maintained by the positive and negative
regulatory activities of many genes. When these genes are mutated to forms that can contribute to
tumorigenesis, either by dominant, gain of function mutations in positive regulators or recessive, loss
of function mutations in negative regulators, they are termed oncogenes or tumour suppressor genes,
respectively. Identified human tumour suppressor genes, though still relatively few in number, are
found to be active in many different cellular processes. I have studied two such genes, the WT1 and
p16 genes, which in their wild type forms are known to contribute to development of the urogenital
system and the mesothelium (WTI) and to control of the cell cycle (pi6).
WT1 was identified as a gene repeatedly disrupted in Wilms' tumour, a common paediatric
renal malignancy. This study is one of many which sought to confirm and understand some of the
roles of WTI in both normal development and tumorigenesis. Mutation analysis of WTI in samples
from patients with sporadic, bilateral and syndrome-associated Wilms' tumour has produced a pattern
of results consistent with the findings of other groups. No mutations were detected in the sporadic and
bilateral tumours, however exonic point mutations were detected in 7 out of 9 syndrome-associated
Wilms' tumour samples that were analysed in detail. Studies examining parental WTI status, genomic
imprinting and allele loss distal to the WTI locus are detailed for the syndrome-associated Wilms'
tumour samples. Additionally, analysis of WTI in samples from patients with testicular tumours or
malignant mesothelioma did not identify any mutations believed to be significant in tumorigenesis.
The contribution, resulting effects and complementary nature of WTI and p16 mutations in
Wilms' tumour and malignant mesothelioma is discussed.