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Werner's Syndrome: What Does An Aging Syndrome Gene Reveal About Cancer?

Mike Miller

The gene for Werner's Syndrome, one of several rare premature aging syndromes with links to cancer, was identified in April 1996. Since then, scientists have been trying to get a better handle on how cancers evolve — based on the unusual cancers seen in patients with this disease.

According to Cheryl Marks, Ph.D., of the National Cancer Institute's Cancer Genetics Branch, "Werner's has given us another indication of a role for genetic instability in cancer. In part, because of the study of Werner's, it is becoming clearer that there are a lot of possible alterations in DNA metabolism that may contribute to the development of cancer."

The discovery of the Werner's gene by Gerard Schellenberg, Ph.D, and collaborators at the Veterans Affairs Puget Sound Health Care System, and Darwin Molecular Corp., Seattle, was viewed as significant not only because it was the first time that any gene associated with aging had been identified, but because it also turned out to be a cancer susceptibility gene, according to David Finkelstein, Ph.D., of the National Institute on Aging's Biology of Aging Program.

Growing List

And the discovery added to the list of syndromes such as Li-Fraumeni and Bloom's that are associated with different cancers and numerous chromosomal abnormalities.

In the past several years, it also has been found that mutant helicase genes have been implicated in some of these syndromes, as originally speculated. Why helicases — enzymes that help DNA unwind — are important in inducing cancers in Werner's patients is not entirely understood, but scientist know that they play a major role in different DNA pathways including replication, recombination, and repair.

One aspect of the disease that fascinates researchers is that Werner's syndrome patients develop a highly unusual spectrum of tumors, including soft tissue sarcomas, thyroid cancers, and meningiomas. One cancer, acral lentiginous melanoma, which occurs on the soles of the feet, is usually very rare but prevalence is 1,000 times higher in Werner's patients than in the general population.

Tumor Spectrum

Most cancers arise in epithelial tissue but Werner's related cancers are more likely to develop in muscle and connective tissue. Why these cancers manifest themselves so distinctly in this syndrome is still very much a mystery but one that might help unlock some of the more puzzling aspects of tumorigenesis.

Another unusual aspect of this disease is that cancers that are often seen in children or young adults occur in Werner's patients in their 40s and 50s (if they live that long; the average lifespan of a Werner's patient is 47 years). Additionally, Werner's is particularly difficult to study because it clusters in inbred families. Since marrying one's first cousin is not a societal norm, Werner's is rare, occurring in only 10 people per million worldwide. As of 1997, only a little over 1,000 cases of Werner's had been identified.

Entry Steps

According to Marks, "we're very much at the beginning stages of teasing out the cancer aspects of these aging syndromes. The Werner's helicase is a very large protein and given the understanding we've gained of the much smaller p53 protein in the past 10 years, I'm guessing that it may take even longer to ferret out many aspects of how the Werner's gene conveys its cancer susceptibility."

Whereas people homozygous for Werner's may fully express the syndrome, said Marks, heterozygotes may never show any evidence of the syndrome, yet still have a slight excess risk for cancer.

The gene for Werner's syndrome is recessive, so the premature aging aspects of the syndrome do not develop unless both copied genes are mutated. The gene may also act in concert with other susceptibility genes to increase a person's cancer risk.

To better understand the Werner's gene, a number of researchers are actively looking at mouse models. But NIA's Finkelstein said that "from an aging perspective, the mouse models are not developing as quickly as we had hoped. What's mechanistic about Werner's is still very much an unknown."

Marks noted that "aging syndromes take a while to develop, but for cancer, animal models may give us much earlier information about malignancies, and may not look exactly like those observed in humans." Of the 10 to 12 distinctive phenotypes associated with human aging that are expressed in Werner's syndrome, she said, if a mouse model expresses just a few of them, that would still be of interest to us.

Larry Loeb, M.D., Ph.D., professor and director of the Joseph Gottstein Memorial Cancer Research Laboratory at the University of Washington, Seattle, is working with a number of different Werner's model systems to try and better understand the role of the gene in maintaining genetic stability.



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Dr. Larry Loeb

 
Opposite Directions

"One of the things we've learned recently is that the [DNA sequence of the] Werner's protein contains both a helicase and an exonuclease [an enzyme that degrades DNA to form mononucleotides whereas a helicase unwinds double-stranded DNA]," he said. "This provides additional roles for the protein in DNA replication, repair, or recombination, or all of the above, but we don't have enough evidence to be sure of any of these yet."

The fact that the Werner's protein contains a helicase "makes it attractive for a DNA replication model." However, Loeb said, "because the helicase works in one direction of the gene while the exonuclease works in the opposite direction, and because these two separate domains seem to be working in quite different ways, we're very busy now trying to figure out their exact functions."

All Werner's mutations shorten or truncate the protein which may also cause a loss of the helicase and/or the exonuclease. These changes could help researchers such as Loeb gain a better understanding of which mutations induce cancer.

None of the mouse models for Werner's that have been reported result in diseases or symptoms applicable to Werner's, as of yet.

One lead, however, has been a comparison between aging syndromes. According to Loeb, researchers have found that Bloom's, a premature aging syndrome that exhibits a high rate of leukemias, has an enzyme that can unwind tetrahelical DNA, the kind found in the end strands of DNA, or telomeres. However, the Bloom's gene doesn't code for an exonuclease and this may explain, in part, why Bloom's and Werner's have very different cancers. Perhaps the actions or lack of exonucleases may be the clue to lead scientists to a better understanding of why and how different cancers develop.

Window of Opportunity

Marks said that "by identifying and working with the aging genes that confer cancer susceptibility, scientists gain a window of opportunity into cancer prevention.

"It is a subtle and hard process to tweak out susceptibility," he said. "But the infrastructure is being built to allow for a more sophisticated analysis of why one person is susceptible, and another is not."



             
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