The University of Texas MD Anderson Cancer Center
Department of Genetics
My research program focuses on identifying and understanding the normal function of genes whose alteration is a critical step during the development of Wilms tumor (WT), a childhood cancer of the kidney. One Wilms tumor gene, WT1, has been isolated, and we have identified germline and somatic mutations at this locus in roughly 20% of Wilms tumor cases. WT1 encodes a zinc finger transcription factor that is essential for normal embryonic development. Children heterozygous for germline WT1 mutations often display genitourinary anomalies and, depending upon the mutation, early onset renal failure.
We are investigating WT1 function in tumorigenesis and development using a combination of approaches, including mutational analysis of primary human tumors, development of mouse strains carrying WT1 mutations observed in humans, kidney organ culture, and gene expression arrays. From this work we know that WT1 mutations are strongly associated with alteration of the wnt signaling pathway and that WT1 mutation results in a distinctive gene expression profile and loss of heterozygosity profile in tumors. We have generated a mutant mouse strain carrying a common missense mutation observed in WT patients Wt1 R394Wand have determined that heterozygous mutant mice develop early onset renal failure with a pathology and disease course identical to that in patients. We are now using this model to identify the early changes in gene expression that initiate the process of glomerulosclerosis and renal failure. We have also generated a mouse strain carrying a conditional knock-out Wt1 allele and are using this strain to investigate the role of Wt1 in the development and subsequent normal function of the kidney, ovaries, and testes.
My laboratory has also determined that WT1 is not responsible for the Wilms tumor predisposition observed in most WT families, demonstrating that predisposition to Wilms tumor is genetically heterogeneous. We have successfully localized to chromosome 19q the gene (FWT2) responsible for inherited predisposition to Wilms tumor in many families and are now sublocalizing it with the goals of isolating the gene, elucidating its role in normal and tumor development, and understanding its role in tumorigenesis. Overall, these studies will help to elucidate the genes and cellular pathways critical for the regulation of cell growth and differentiation in normal kidney and how those functions are abrogated during tumorigenesis.
Education & Training
Ph.D. - University of Michigan - 1987
human genetics; cancer genetics; familial cancer predisposition; kidney development