An ability to detect specific genetic mutations in virtually 100% of family members with the hereditary disorder known as von Hippel-Lindau syndrome is enabling researchers at the National Cancer Institute to begin matching these defects to the clinical course of their disease. Mutations in the VHL gene, first identified by NCI scientists in 1993, predisposes individuals to benign and malignant tumors in a variety of organs.
And the next step is well under way: detecting which organs will be affected, and which cancers are unlikely to develop at all, in order to speed up diagnosis and to provide early treatment, where appropriate.
"We're beginning to make some predictions, although we'd like to do better," said W. Marston Linehan, M.D., chief of urologic surgery in NCI's Division of Clinical Sciences. "This is a complicated and ongoing work."
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Still, molecular profiles have begun to emerge.
For example, families who develop pheochromocytomas, a tumor of the adrenal glands, said Berton Zbar, M.D., chief of NCI's Laboratory of Immunobiology, have a high likelihood nearly 80% of having a missense mutation or a single amino acid substitution in a particular region of the VHL gene.
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On the other hand, some missense mutations in the VHL gene can lead to families that get mostly pheochromocytomas and almost nothing else. "Other families studied have a [missense] mutation, and they get pheochromocytoma and retinal angiomas, but they don't get renal carcinoma or meningioblastoma," said Stolle whose laboratory has tested about 700 tissue samples from NCI and other institutions over the past 3 years.
These clinical variations are being sorted out and compiled into a database, begun in 1996. The database is accumulating information from 174 VHL families and more than 600 family members who have been studied at the NCI for a decade or more. The 2-year-old initiative will correlate specific VHL gene mutations with the phenotype or types of tumors that develop. "We expect our initial analysis to be completed within [another] 2 years," said Linehan.
One reason that a database allowing for early diagnosis is so important, Linehan stressed, is that "We have had families where children as young as 6 have had pheochromocytomas and where children under 10 have developed and died of brain tumors. I think the message here is early screening, so you can do early diagnosis, and in some cases, recommend intervention."
VHL mutations occur in an estimated one in 36,000 births. Children of affected individuals have a 50% chance of inheriting VHL, whose earliest manifestation is often the occurrence of retinal angiomas a highly vascular tumor of the eye in late childhood or early adolescence. But in some individuals, Linehan said, "it is surprising that some clinical manifestations are detected so late in life."
Having the VHL gene, however, doesn't necessarily spell doom. Some families with VHL mutations will not develop disease at all or will develop only mild disease, said Zbar who with Michael Lerman, M.D., Ph.D., collaborated with Linehan on the disease-gene isolation effort in 1993. Zbar said that the clearest example researchers have so far of this is a mutation known as 505. Families with the 505 genetic mutation have what geneticists refer to as "reduced penetrance" meaning only a small portion of them will develop disease, he said.
Early Removal
Moreover, because some tumors associated with VHL are slowgrowing, many surgeons opt to remove tumors in the kidney and elsewhere only when they reach a certain size. Some patients, as a result, Linehan said, can lead comparatively normal lives once a diagnosis is made.
But many VHL-associated tumors create major problems, such as paralysis when central nervous system tumors develop, or blindness associated with retinal angiomas. "There are several families where we traced the gene by family history, even though the medical records were lost," said Stolle. In one family the grandchild, asked about his grandmother's blindness, said, "I remember going to her house as a child, and there was a string from the back door to the outhouse, so that she could find her way there."
In finding these VHL families and testing for the various mutations of the gene, there are questions about whether such families can cope with the knowledge, and whether they'll lose their health insurance as a result.
Deborah Collins, a genetic counselor at the University of Kansas Medical Center, who counsels 12 VHL families, three of whom have over 200 members, said, "Most are very comfortable with their disease. They have an internal family support system." She said most come in, get a tumor removed, and afterward continue their usual activities after perhaps missing a few weeks of work.
Insurance Worries
There is a continuing worry over insurance, though, she admitted. She said one patient who had lost perhaps a month of work over an 18-year period because of VHL did lose her insurance even though she was an insurance underwriter.
Insurance problems were also an initial problem for 32-year-old Jay Platt of Valdosta, Ga., who was drummed out of the Marines after 14 years following a partial nephrectomy for kidney cancer and removal of a retinal angioma. He was originally denied continued health insurance because his ailments were not service connected, as he explained in an issue of the VHL Family Forum, a patient newsletter.
The Marines reconsidered, however, reinstating his health insurance. And at last report, Platt was hiking the length of the Appalachian trial in order to raise money for research for VHL. He planned the hike, he said, despite having bilateral kidney tumors, a tumor in the cerebellum, and multiple cysts on his pancreas and spinal cord.
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