Scientific Overview: Cancer Genetics
Research Interests
Kidney cancer, or renal cell carcinoma (RCC), is the tenth most common cancer in the United States (35,000 new cases and more than 13,000 deaths a year). Its incidence has been increasing, a phenomenon that cannot be accounted for by the wider use of imaging procedures. We have established a comprehensive and integrated kidney research program, and our major research goals are 1) to identify the molecular signatures of different subtypes of kidney tumors, both hereditary and sporadic, and to understand how genes function and interact in giving rise to the tumors and their progression; 2) to identify and develop diagnostic and prognostic biomarkers for kidney cancer; 3) to identify and study novel and established molecular drug targets and their sensitivity and resistance; and 4) to develop animal models for drug testing and preclinical bioimaging.
Our program to date has established a worldwide network of collaborators; a tissue bank containing fresh-frozen tumor pairs (over 1,000 cases) and serum; and a gene expression profiling database of 500 tumors, with long-term clinical follow-up information for half of them. Our program includes positional cloning of hereditary RCC syndromes and functional studies of their related genes, microarray and bioinformatic analysis, generation of RCC mouse models, and more recently, molecular therapeutic studies.
Hereditary RCC syndromes
We are currently focusing on the cloning of the gene responsible for familial clear cell renal cell carcinoma, which is a separate entity from von Hippel-Lindau (VHL) and from familial RCC with a chromosome-3 translocation. These efforts involve the use of high-density, single-nucleotide-polymorphism (SNP) microarrays and correlation with our existing gene expression profiles.
Microarray gene expression profiling and bioinformatics
High-density SNP genotyping has been performed on some of the specimens registered in our RCC expression database. We are currently focusing on analysis and data mining. Clinically, we continue to subclassify the tumors by correlation with clinicopathological information. One example is the study of the unclassified group of tumors for which the histological diagnosis is “unknown”. We have also identified a specific set of genes that can distinguish chromophobe (malignant) from oncocytoma (benign), two types that share a high degree of similarity in their expression profiles. Our database has proven to be very useful in RCC research, since we can obtain differential expression of any gene in seconds; this has led to numerous collaborations. We are currently combining SNP and expression data to identify novel RCC-related genes.
Mouse models of kidney cancer and molecular therapeutic studies
We have generated several kidney-specific conditional knock-outs including APC, PTEN, and VHL. The first two knock-outs give rise to renal cysts and tumors, whereas VHL remains neoplasia-free; double knock-outs are also being studied. We have successfully generated nine xenograft RCC models via subcapsular injection that have characteristic clinical features and outcomes. Tumors and serum have been harvested for a baseline data set. We are currently performing in vitro and in vivo studies on several new drugs for kidney cancer.
Molecular and cellular studies
We use numerous well-characterized kidney cancer cell lines to study the functions of novel kidney cancer–related genes by overexpressing or down-regulating the genes. In addition, we perform cell cycle, proliferation, and migration assays to assess the cellular effects of these genes. These studies are usually coupled with in vivo studies.
External Collaborators
We have extensive collaborations with researchers and clinicians in the United States and overseas.