OHSU plays role in disease breakthrough

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Oregonian, The (Portland, OR)

September 16, 2003

Author: Andy Dworkin - The Oregonian

Researchers gain a key insight to mechanisms behind Fanconi anemia, a disease affecting the family of UO's president

Scientists in Portland and elsewhere just won their first solid insight into how a flawed genetic system can cause some cancers and Fanconi anemia, a rare disease that affects Oregon's noted Frohnmayer family.

The discovery also could shed new light on why the body starts to break down as people age, researchers said.

Researchers already had found a number of genes linked to the rare disease, working partly with money from the Frohnmayers' Eugene-based Fanconi Anemia Research Fund. Last year, for instance, Oregon Health & Science University's Dr. Markus Grompe showed that a gene known to influence breast cancer was also part of a system that caused some children to have Fanconi anemia.

Scientists have had little idea how those genes, and the proteins they make, actually create the disease: They knew the start and end points, but not the path between the two.

But a paper published online Monday by Nature Genetics (www.nature.com/ng) identifies a new protein and shows it plays a known role. The protein helps complete a chemical change that helps a final gene fix flawed DNA. When the protein isn't made properly, as in Fanconi anemia, DNA mutations can snowball into cancers.

"This gives us a familiar landmark" to use to explore the rest of the Fanconi system, said Maureen Hoatlin, one of two OHSU researchers involved in the study, along with Michael Wallisch. "I think we're entering another era for Fanconi research."

That has significance beyond the rare but deadly genetic disease, which affects at least 500 U.S. residents. The same process of fixing broken DNA that underlies Fanconi anemia also seems to play a big role in many cancers, such as ovarian cancer and acute myeloid leukemia. And it is linked to aging.

"Some scientists theorize that DNA damage, which gradually accumulates as we age, leads to malfunctioning genes and deteriorating tissues and organs as well as increased risks of cancer as years go by," Weidong Wang, a National Institute on Aging scientist involved in the study, wrote in a statement. "So every time we learn something more about DNA repair, we can hope to use that new knowledge to find ways to prevent the excessive damage to DNA that appears to occur with aging."

In every body, DNA breaks or mutates as cells grow and divide. The body has systems to find and stop those problems quickly -- similar to the way computers have software to halt viruses before they become problems.

When one of the body's DNA-screening systems breaks, mutant DNA can copy itself out of control and cause cancer -- as bad screening software can let a virus infect a computer, copying itself and sending out more viruses.

Grompe found a Fanconi gene, called FANCD2, that seems to be the main player at the end of one DNA-fixing system, or "pathway." Researchers think other genes lie "upstream," making proteins necessary for FANCD2 to work. They know Fanconi anemia happens when a person inherits two bad copies of any of these genes -- but don't know exactly how.

Although the new study doesn't describe the full DNA-repair pathway, it identifies the protein that adds a special molecule to the protein made by FANCD2. That molecule is critical for it to be able to work on DNA.

Tracking back from the PHF9 protein, scientists found the gene that makes it. That brings to eight the number of genes known to be involved in Fanconi anemia, Hoatlin said.

Lynn Frohnmayer, co-founder of the Fanconi fund, said the researchers found three other proteins involved in the process that have not yet been linked to genes. That means they soon might find three more Fanconi genes, she said.

Fanconi anemia has affected three daughters of Frohnmayer and her husband, University of Oregon President David Frohnmayer. Their older daughters, Kirsten and Katie, died of complications of the disease. Their youngest daughter, 16-year-old Amy, is a junior in high school.

"She's very, very stable" with just a small daily dose of medication to maintain her blood health, Lynn Frohnmayer said of Amy.

Frohnmayer said the Eugene-based fund has given grants to three of the scientists involved in the new study. That is part of more than $6 million the fund has awarded to 30 labs worldwide, much of which "has come from the generosity of the people of Oregon," she said.

The grants have helped further basic knowledge about how genes and proteins cause the disease -- crucial for finding better treatments or a cure, Frohnmayer said.

"This seems like a key," she said of Monday's publication. "If you don't understand the problem, and how these genes work in a normal person . . . you don't have much hope for finding a rational therapy."

Copyright (c) 2003 Oregonian Publishing Co.