Wilms' tumor, a childhood malignancy of the kidney, is one of the most common pediatric tumors. The disease occurs in both sporadic and hereditary forms and is associated with a number of congenital disorders. Wilms' tumor appears to be genetically heterogeneous although only a single Wilms' tumor suppressor gene, designated WT1, has been isolated to date. WT1 encodes a zinc finger protein and is mutated in a subset of Wilms' tumors and in patients with Denys-Drash syndrome (DDS), an association of Wilms' tumor and severe genitourinary defects. This thesis reports a mutational analysis of WT1, detailing the spectrum and frequency of mutations in sporadic Wilms' tumors. Most WT1 mutations were homozygous and were predicted to cause premature termination of translation, suggesting that tumorigenesis associated with WT1 involves a two-hit mechanism. The mutational status of WT1 was determined in patients with variable expressivity of the DDS phenotype in order to assess potential genotype/phenotype correlations. Patients with less severe developmental anomalies had germline mutations predicted to result in truncated WT1 proteins, while those with full manifestation of DDS were characterized by missense mutations in the zinc finger region. This demonstrates that different mutations in WT1 are associated with specific effects on genitourinary development. / We investigated the biochemical properties of WT1 and assessed the effects of some naturally occurring mutations. A number of studies have provided evidence that WT1 may be involved in RNA metabolism. We used an iterative selection method to identify potential RNA ligands to WT1. Specific, high affinity ligands were isolated. Mutational analysis elucidated structural features necessary for the RNA-protein interaction. These ligands may reflect RNA sequences targeted by WT1 in vivo. / Since our studies demonstrated that WT1 mutations are restricted to a minority of Wilms' tumors, the understanding of mechanisms underlying Wilms' tumorigenesis required the identification of other genes which contribute to this malignancy. We studied the involvement of the p53 gene tumor suppressor, a critical regulator of abnormal cellular growth and genetic stability. P53 mutations were restricted to the rare anaplastic subtype of Wilms' tumor, a genetically unstable histological variant associated with poor prognosis and resistance to therapy. P53 mutations occurred as late events, associated with malignant progression. The association of p53 mutations with anaplasia allows rationalization of the clinicopathological features of this histological variant, indicating that p53 may regulate genome integrity and chemosensitivity of human cancer cells in vivo.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.34911 |
| Date | January 1998 |
| Creators | Bardeesy, Nabeel. |
| Contributors | Pelletier, Jerry (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001635577, proquestno: NQ44356, Theses scanned by UMI/ProQuest. |
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