Molecular Cloning of the Wilms tumor Gene from 7p15-21

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DESCRIPTION (provided by applicant): Wilms tumor is pediatric lesion of the kidney and is one of the most common solid malignancies of the childhood. Disease can occur in one or both kidneys, approximately 8% of cases being bilateral. The suggestion of a genetic component in the etiology of the tumor has come from several observations. Firstly, bilateral disease is associated with an early age of onset. Secondly, there is a high incidence of bilateral tumors in cases with a family history of Wilms tumor and in patients with associated congenital anomalies. Histological features indicate that the tumor occurs as a result of aberrant embryological development of the kidney. The kidney is therefore a model for studying the association between processes involved in tissue development and predisposition to malignancy. Although a gene for Wilms tumor (WT1) has been cloned, less than 10% of cases could be explained by mutations and/or alterations of this gene. Several other loci have been implicated in the etiology of Wilms tumors, including the 7p15-21 locus which was shown to be involved in 15-25% of Wilms tumors cases, strongly suggesting that a tumor suppressor gene for this disease must lie within this region. Since homozygous deletions are hallmarks of tumor suppressor genes, a homozygous deletion has been described in a Wilms tumor within the 7p15-21 locus and we have now characterized the extent of this deletion as a first step towards the identification of the Wilms tumor suppressor gene using a very powerful mutation analysis technology (DHPLC) and a large cohort of Wilms tumors, including those tumors that we have identified to show loss of heterozygosity at the 7p15-21 locus. By studying the expression pattern of this gene we will be able to identify the population of stem cells which give rise to these tumors. Understanding the nature of the genetic events which allow these cells to escape their normal growth regulation may also provide an opportunity for therapeutic intervention.