Von Hippel-Lindau Disease, an Inherited Cancer Syndrome

Dr. James Gnarra

The association between chromosome abnormalities and cancer is nearly 100 years old. Although the association between chromosomal abnormalities and human cancers was first made in the early 1900's, the first genetic marker for a cancer, the Philadelphia chromosome that occurs in chronic myelogenous leukemia, was not identified until 1960. Research that demonstrated the association of specific genes with certain cancers did not flourish until the 1990's. Although this seems like an incredibly slow progression of discoveries, we know a tremendous amount of information about cancer and chromosomes today. Much of this progress has been made through research in cancer genetics, with a major emphasis on identifying families in which members had a clear predisposition to developing certain types of cancer.

The importance of understanding the role that genetics has played in the identification of cancer-associated genes can be appreciated through a comparison of lung and kidney cancers. Each of these cancers has a strong association with smoking, and each exhibits common abnormalities of human chromosome 3. Lung cancer, with an estimated 170,000 new cases diagnosed in the United States in the year 2001, does not appear to have a hereditary component. In other words, families with a predisposition to developing lung cancer in the absence of smoking have not been identified. On the other hand, about 2% of the ~31,000 new cases of kidney cancer diagnosed in the U.S. in 2001 were hereditary cancers. These kidney cancers occurred in patients who were predisposed to developing kidney cancer because of their family history. Through the study of families with cancer predisposition, researchers have identified several genes associated with the development of kidney cancer, while lung cancer genes have not been defined.

There are several types of inherited kidney cancer. One is kidney cancer associated with von Hippel-Lindau (VHL) disease. By analyzing genetic markers in many VHL patients, it was discovered in the late 1980's that the gene responsible for VHL disease occurs on human chromosome 3. The VHL gene was identified in 1993 and was found to be mutated in patients with VHL disease. In addition, patients with non-hereditary kidney cancer were found to have mutations in the VHL gene in their tumors but not in other cells in their body. Therefore, mutations in the VHL gene are closely associated with kidney cancer. This is an example where the identification of a gene responsible for a rare inherited cancer led to the understanding that the same gene is responsible for the more common, non-inherited form of the same cancer.

VHL disease is a cancer syndrome. VHL patients may develop cysts or tumors in the kidneys, retinas, brain, spinal cord, adrenals, pancreas, inner ear, or the scrotum. Before the VHL gene was identified in 1993, diagnosis was determined by family history and the presence of multiple tumors. Because diagnoses were frequently made in the late stages of cancer growth, VHL patients had a significantly shortened life expectancy. Today a relatively simple DNA-based blood test can identify VHL disease gene carriers before any tumors are detected. While we can readily identify patients predisposed to developing VHL disease, we cannot yet predict the full spectrum of tumors these patients will develop or at what age they will become problematic. Therefore, VHL patients require frequent and detailed medical examinations to detect tumors and follow their growth.

A VHL patient has a 50-50 chance of passing a mutated form of the VHL gene to each of his or her children. The VHL gene produces a protein that works as a tumor suppressor. Tumor suppressors control cell division, and when tumor suppressors are mutated, they lose their normal function and cells may exhibit uncontrolled growth. Since the VHL tumor suppressor is mutated in most cases of kidney cancer seen in the general population, gaining an understanding of how the VHL tumor suppressor works will help VHL patients as well as patients with non-inherited kidney cancer.

The possibility of developing cancer is something that every person fears to some degree. For some, such as VHL patients, it is not a matter of if they will develop cancer but rather when it will occur. With genetic testing and close medical surveillance, we expect that the life expectancy of a VHL patient diagnosed today will far exceed the life expectancy of a patient diagnosed as recently as 10 years ago. It is the goal of future biomedical research to develop and offer therapies that are even more effective to VHL and non-hereditary kidney cancer patients.


Here are answers to some common questions regarding VHL Disease and other types of inherited cancer:

I'm 55 years old, and after I went to the doctor about having blood in my urine 7 years ago, I was diagnosed with kidney cancer. If kidney cancer can be inherited, should I have my children tested to see if they have a mutation in the VHL gene?

Probably not. If you have no family history of kidney cancer or any of the spectrum of tumors associated with VHL disease, if your kidney cancer was a single tumor in one kidney, and if you have no other tumors, then it is likely that your cancer was what we call a non-hereditary or sporadic cancer. This would mean that your children would have no greater likelihood of developing cancer than anyone in the general population.

My father died of lung cancer when he was 56 years old and his brother died of lung cancer when he was 60 years old. If cancer can be inherited, should I be concerned about developing lung cancer too?

Yes, if you are a smoker. There is no indication that lung cancer is inherited, but it does have a very strong association with smoking. Researchers do not yet understand why some smokers develop lung cancer while others do not, or why in some very rare cases non-smokers develop lung cancer. Genes are almost certainly the determining factors in lung cancer predisposition, so you should be concerned about developing lung cancer if you smoke.

I am a 23-year-old woman and my mother recently died from kidney cancer related to VHL disease. We did not know she had VHL until just before her death. I had genetic testing done, and a VHL mutation was found in my blood cells. When I had a full medical work-up, I learned I had several tumors in my brain and in both kidneys. My family doctor told me that I should not have children, because they would be subjected to the same cancers that I have. Is this true?

Any VHL patient has a 50-50 chance of passing the mutated gene onto their children. This is a personal decision that you need to make for yourself, but you can help make a better decision with some education about VHL. The VHL Family Alliance (www.vhl.org) is a patient support organization that can provide information on VHL disease and can put you in touch with other VHL patients. Children can be tested at any age to determine whether they inherited a mutated form of the VHL gene. If a child or other family member has a mutated VHL gene, careful, annual medical screening will enable physicians to identify tumors and follow their growth before they become problematic. New surgical techniques are continually being developed, and drugs that may limit tumor growth are currently being tested. Through patient education and biomedical research, VHL patients may lead long, normal lives.

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