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Drs. Linehan and Zbar have worked together for more than two decades on determining the molecular basis of kidney cancer in order to provide the foundation for finding more effective treatments. They talked with the NCI Cancer Bulletin about where they have been and where this research is headed.

Can you talk about the role of studying families in your work over the years?
Dr. Linehan: In the mid-1980s, we showed loss of chromosome 3 in patients with sporadic kidney cancer, and we published a paper in Nature saying that this could indicate there is a cancer gene in this location. But it was just going to take too long to find the gene at the rate we were going. Dr. Al Knudson, who pioneered the study of genetics in cancer, suggested that looking at families with hereditary forms of kidney cancer would help us identify the gene.

Dr. Zbar: We sent letters to physicians in the United States and Canada to recruit families with hereditary renal carcinoma. Physicians were targeted based on the specific clinical characteristics of the disease under study. I worked with a small NCI team to evaluate renal carcinoma families, which included conducting detailed medical histories and collecting blood samples for DNA analysis at our laboratory at NCI-Frederick.

We then set up a large, multidisciplinary team to evaluate patients. We constructed family trees and performed genetic mapping, then physical mapping in the hope of finding the disease genes. We've seen families from all over this country and, really, all over the world.

After everything that's been accomplished, is it now just a matter of seeing which agents are most effective in clinical trials?
Dr. Linehan: I'm not naïve about the tenacity of these tumors. As a clinician who has managed patients with metastatic disease, I believe that by studying the pathways and testing the agents that block those pathways, we have a very good plan for progress.

Dr. Zbar: It would be extremely useful to identify molecular markers to determine which patients will be the best candidates for the various targeted treatments. The presence (or absence) and specific type of somatic VHL mutation would be one genetic alteration that might predict response of metastatic renal carcinomas to drug therapy.