Spotlight

Dr. Berton Zbar,
Laboratory of Immunobiology

Spotlight Archive

“We make house calls!”

Not many doctors, let alone research scientists, can make that claim. But Dr. Berton Zbar, Chief of the Laboratory of Immunobiology, Center for Cancer Research, NCI-Frederick, does so with delight. Since 1985, he and his colleagues have been studying families affected with the von Hippel-Lindau syndrome (VHL), hereditary papillary renal carcinoma (HPRC), the Birt-Hogg-Dubé syndrome (BHD), and most recently, Hereditary Leiomyoma Renal Cell Carcinoma (HLRCC). In the last 15 years, they have evaluated nearly 2,000 members of kidney cancer families.

Finding rare families affected with kidney cancer can be difficult and time-consuming. Every 8 to 12 months, Dr. Zbar requests patient/family referrals from physicians and specialists nationwide. Dr. Zbar noted that NCI-Frederick’s Scientific Publications, Graphics & Media (SPGM) has been an integral part of this stage of the research effort, preparing the letters and composite photographs and organizing the mass mailings to specialists such as dermatologists (because BHD involves the skin), urologists (VHL—kidney) or ophthalmologists (VHL—eye). He then interviews the referred patients to determine their suitability for the studies.

The studies involve close collaboration with Dr. Marston Linehan, a urologic oncologist, and other researchers at NIH, as well as researchers in Canada and sometimes Europe. This work requires the participation of physicians with a wide variety of skills. Dermatologists, pathologists, radiologists and ophthalmologists all contribute to the success of the program. Dr. Zbar’s current field trip team includes a nurse/genetic counselor, who advises the patients about the risks and benefits of participating in genetic research; when the team studied the Birt-Hogg-Dubé condition, they included a dermatologist to do skin biopsies.

Depending on family size, the interviews, medical histories, and blood or tissue sampling may be completed in four or five hours, usually on a weekend. The research group travels all over the United States and Canada. Just this year, they’ve visited Portland, Maine; San Antonio, Texas; Edmonton, Alberta, Canada; Rochester, New York; and Manchester, New Hampshire, to name a few.

“The idea that you have a giant government institution in Washington and that its doctors visit people in any place that you can possibly imagine is exciting,” Dr. Zbar said, describing a trip to a patient with bilateral kidney cancer. Because of inclement weather, the patient had not wanted to travel; therefore, they went to him. “Four of us drove through the farm roads in northern Iowa, and I said to myself, ‘This is really marvelous!’ We had brought NIH to this guy’s door, and we can bring him the benefits, and it was just really, really special.”

Another important aspect, aside from making house calls, is that all the patients, whether or not they come to NIH, are entered in the clinical protocols for which Dr. Linehan is approved. The rules governing NIH protocols are strict. At NIH, the patients “get sort of a ‘soup to nuts’ clinical evaluation… and [their] participation… makes a big difference in the studies because you can do a much more in-depth exam in the hospital than you can on the road. The government pays for their round-trip transportation, medical tests, and a small per diem; the patients pay for their lodging and food. It’s wonderful.”

Dr. Zbar added that often, the families keep good genealogic records, which are helpful in determining what diseases different family members died from.

Hand-in-hand with the genealogic records, genetic testing is, of course, one of the main thrusts of the studies. Sometimes, the researchers can pinpoint the start of a disease. For example, Dr. Zbar described a VHL family in which testing revealed that neither of the source patient’s parents had the gene, although the patient transmitted the condition to one of her three daughters who, in turn, had a baby that genetic testing revealed also had VHL. “From a variety of tests we know that this is a new genetic change…. Genes mutate and… sometimes… make this disease.” The leaps in genetic knowledge have been useful in many ways, even though cures have not been found for many diseases.

In more than one case, genetic testing identified an earlier physician’s incorrect diagnosis of VHL. For example, three people with the condition in one family had been referred to Dr. Zbar; however, testing revealed that while two indeed had the mutation, the third, a child, didn’t. “So, this was an incorrect diagnosis that was reversed, based on the DNA testing….That was kind of nice.”

Another disorder that Dr. Zbar and his colleagues have worked on, along with BHD, is Hereditary Leiomyoma Renal Cell Carcinoma (HLRCC). “The thing that’s interesting about those disorders is...these are two distinct diseases that have inherited tendencies to get tumors in the skin and they also get kidney tumors. And that’s why we study them.”

Currently, Dr. Zbar said, the only effective treatment for tumors of the kidney is surgical removal. In von Hippel-Lindau disease the vascular tumors found in the eye are treated by laser ablation. The central nervous system vascular tumors in patients with von Hippel-Lindau disease are treated by surgical removal.

VHL, the most common form of inherited kidney cancer, “is probably the worst of the diseases because you get tumors in your brain, your spinal cord, your kidneys, your adrenal glands; and they keep coming. It’s not that you just get one, but that you get these tumors repeatedly in the kidney, brain and spinal cord. So it is a 4-plus nasty disease. In the old days, that is, pre-gene discovery, the advice was that each of the children of an individual who had this had to be examined periodically…to detect the lesions early and treat them. [Discovery of the gene] meant that [the doctor] could identify which of [the patient’s] children had it and [screen only those] children,” enabling doctors to focus medical care on those who really need it.

“These conditions [BHD and VHL]…have a very strong inherited component…but…another variety of kidney cancer in families…[combines] environmental and genetic factors. We call this Familial Renal Carcinoma, and that is the condition that we are going to study with Mike Dean [See the March Spotlight article in the NCI-Frederick archive]. We completed the gene investigations for the Birt-Hogg-Dubé and completed it for this Hereditary Leiomyoma condition, but what we call Familial Renal Carcinoma is just at the very start…

“I would like to develop a statistical tool to estimate risk for individual people getting kidney cancer, based on things like smoking, weight, height, and eating habits, and other things. Most of the people in the lab are working on the BHD protein, which we call folliculin, and trying to figure out…what it does and how it works, why it produces kidney tumors when it is not working right.

“Another interesting fact is that there are inherited types of kidney cancer in rats and in German Shepherds that appear to be due to mutations in the BHD gene…It has not been proven that these conditions in the rat and the dog are due to mutations in their version of the BHD gene. It is just that the data points that way now. We have developed a way of producing something like Von Hippel-Lindau disease in mice.”

Echoing the goal of the NCI to make cancer uncommon and easily treatable, Dr. Zbar noted that research is not finished until “we can use that information for an effective therapy or a cure. Until that is accomplished, there is plenty more to do.”

For further information about the Laboratory of Immunobiology’s research, log onto http://ccr.cancer.gov/labs/lab.asp?LabID=100 or http://web.ncifcrf.gov/research/kidney.

Article by Maritta Perry Grau
Photography by Jonathan Summers
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
Web Graphics and Development by Jim Miller
Computer & Statistical Services
National Cancer Institute at Frederick