VHL Gene Linked to Kidney Cancer

A study published in the May issue of Nature Genetics shows that the VHL gene plays a role not only in the formation of tumors in people who inherit a flaw in the VHL gene, but also in 85% of the kidney cancers in the general population as well. The cancer, called sporadic (non-familial) clear cell carcinoma, accounts for about 23,500 newly diagnosed cases of kidney cancer each year in the U.S. alone.

"With identification of this kidney cancer gene, it will be possible to develop new methods to improve the diagnosis and treatment of the disease and potentially to find ways to prevent it," said W. Marston Linehan, M.D., of the Surgery Branch, National Cancer Institute (NCI). "The finding also will make it possible to develop a blood or urine test that can detect kidney cancer early when it is most treatable." When detected in its earliest stages, the survival rate is 86%.

The damaged or mutated gene responsible for sporadic clear cell carcinoma of the kidney is a tumor suppressor gene located on the short arm of chromosome 3. The protein produced by the gene appears to normally restrain growth. The researchers found that this gene is mutated (inactivated) in a high percentage of tumors (57%) from patients with sporadic, non-familial cancer.

This is the same gene that was identified last year as the cause of the inherited cancer syndrome von Hippel-Lindau (VHL) disease.

"The disease appears to fit the two-hit model for development of cancer, where both copies of the critical gene are damaged or mutated," said co-investigator Berton Zbar, M.D., chief of NCI’s Laboratory of Immunobiology.

Everyone has two copies of the VHL gene, as they do of every gene — one from the mother and one from the father. When we say that a person has VHL, that means that they inherited the faulty copy of the VHL gene from the parent who has VHL. One normal copy of a gene is sufficient to prevent development of a tumor. If both copies are damaged or mutated — the two-hit model — cancer may develop.

In people in the general population, the two copies of the VHL gene they inherit are both healthy. In order for a tumor to form, both copies of this gene must become deactivated. There are numerous theories of how genes get changed — environmental factors, water pollution, cigarette smoke, radiation, free radicals, etc. — we don’t understand just what happens, but step by step the process is becoming clearer.

From the work on the VHL gene previously reported by Latif, Lerman, Zbar, et al.² we know that the VHL gene is on chromosome 3p. This article reports that the gene has been cloned by the same team³ and that an article reporting the cloning has been submitted for publication. Now that the gene has been cloned, scientists can make greater headway in understanding how the gene operates. The gene appears to be important in encoding a functional protein. The next step is to understand what this protein does in the body, and what occurs when it is not present.

It is as if it takes two occurrences for a tumor to grow and become cancerous. First, the brakes have to be off; second the accelerator has to be on. The disabling of the VHL gene takes off the brakes. But what puts the accelerator on?

The researchers also found that the kidney cancer gene is affected early in the development of the disease. This finding is important, Dr. Linehan explained, because its early presence makes it possible to consider development of treatments to halt or reverse the progression of the disease in its early stages.

All this implies that exposure of the kidney to environmental carcinogens may lead to mutation of the VHL gene and subsequent tumor formation. This demonstration that mutations in the VHL gene foster tumor growth in renal cell carcinoma "should lead to a better understanding of how renal epithelial cell growth is regulated and should aid in methods of diagnosis and treatment of patients with this malignancy."⁴

For people with VHL, what do we learn from this?

We learn that VHL kidney tumors are indeed closely related to renal cell carcinoma. But we also learn that there is more to be learned. Dr. Linehan tells us, for example, that while he can get 80% of sporadic renal cell carcinoma tissue to grow in the lab, he has been unable to get VHL kidney tumor tissue to grow there. He still does not understand why. We know that VHL takes the brakes off, but what presses the accelerator? The same environmental factors which cause the VHL gene to change affect both people with VHL and people with sporadic kidney cancers.

1. J. Gnarra et al, "Mutations of the VHL tumour suppressor gene in renal carcinoma," published in Nature Genetics, May 1994, pages 85-90. This research was conducted by Drs.Berton Zbar, Michael I. Lerman, and Marston W. Linehan of NCI in collaboration with the Urology Departments of New York Hospital; Cornell University Medical Center, New York; University of Michigan, Ann Arbor; and Johns Hopkins Medical Institutions, Baltimore; Laboratory of Molecular Pathology, Technical University Munich; University Clinic of Surgery, Heidelberg.

2. F. Latif et al, "Identification of the von Hippel-Lindau disease tumour suppressor gene." Science, 260, 1317-1320 (1993). Reported in VHLFF, June 1993.

3. F. Chen et al, manuscript submitted.

4. Gnarra et al, p. 90.