Frederic Waldman, MD, PhD

Research Interests

Our research activities are focused on exploring the significance of genetic alterations in human malignancies. We are studying progression of solid tumors, based on a model of tumor progression in which tumors are the evolutionary product of an accumulation of genetic events, i.e. mutations, deletions, or amplifications in cellular oncogenes or tumor suppressor genes. Each tumor is unique in the events which lead to its development and progression. By studying the pattern of genetic aberrations in actual tumors, we can directly test hypothetical models defining interactions among oncogenes and tumor suppressor genes during tumor progression.

We have been applying tools of molecular cytogenetics to investigate the steps of tumor progression. Fluorescence in situ hybridization (FISH) with chromosome and region-specific DNA probes has been used to characterize genetic aberrations in individual tumor cells. This approach allows us to define clonal relationships during tumor development. We have shown a high level of numerical chromosome abnormalities in low stage and low grade tumors (i.e. superficial bladder cancer), suggesting that FISH analysis may be useful as a diagnostic tool to detect the presence of tumor cells in exfoliated cells or fine needle biopsy specimens. Most recently, we are characterizing premalignant changes, showing that genetic instability is a very early event in tumorigenesis.

Comparative genomic hybridization (CGH) has also been used to study the process of genetic progression in solid tumors. CGH allows detection and localization of DNA sequence copy number variation anywhere in the tumor genome. We have used CGH to characterize sequence copy number losses and gains in over 40 cell lines, 150 bladder carcinomas, and 100 renal cancers. We found an association between tumor stage and the number of CGH aberrations, supporting our model of step-wise genetic progression. Especially exciting was our finding of an association between the number of CGH detectable alterations and clinical outcome in stage T3 renal tumors. CGH has also proved very helpful in defining the locations of previously unknown oncogenes and tumor suppressor genes. One such locus, on the long arm of chromosome 20, has become a target for positional cloning.

CGH has also been useful in our studies of early events in tumorigenesis. By careful micro-dissection of archival sections, followed by degenerate primer PCR, and fluorescent labeling, we are able to perform CGH on fewer than 100 sectioned nuclei. This technique has been used to examine changes present in dysplasia of the bladder urothelium, and in renal microadenomas. By characterizing the presence and location of chromosomal changes in the earliest identifiable changes of epithelial neoplasia, we are presenting targets of opportunity for positional cloning and gene-based therapies. CGH is an excellent tool for identifying clonal relationships between tumor specimens. Metastases of bladder primaries showed a strong concordance with their primaries, suggesting that clonal evolution is not as dramatic following metastasis as was previously thought.

Most recently we have been applying techniques of array based CGH to models of solid tumor progression. DNA and cDNA arrays are being used to define at ever higher resolution the genetic alterations present in tumor DNA's and RNA's. We have applied this approach to renal cancers, and have been able to independently define the histopathologic subtype of renal cancer based on genomic changes alone. We have also used array-based CGH to define genomic alterations in bladder cancers, identifying changes which are associated with superficial vs. invasive phenotype. These studies have potential for defining genomic and expression changes which participate in growth control and signaling pathways during solid tumor development and progression.

return to top