Research finds gene link to rare anemia.

Byline: TIM CHRISTIE The Register-Guard

Researchers have discovered that a gene associated with inherited breast cancer is also one of the genes involved in Fanconi anemia, a rare and deadly childhood disease.

The discovery could lead to development of more genetic screening tests to identify people at risk for common types of cancer, and spur interest from drug companies to develop new gene-specific cancer drugs, researchers said.

And it connects the relatively obscure world of Fanconi anemia research with the mainstream of cancer research, University of Oregon President Dave Frohnmayer said.

Frohnmayer and his wife, Lynn, have lost two of their five children to Fanconi anemia. Katie died at age 12 in 1991 and Kirsten died in 1997 when she was 24.

Fanconi anemia is a genetic disorder that wrecks the body's ability to make blood cells in the bone marrow. The resulting shortage of blood cells leaves a body susceptible to infections, bleeding and exhaustion. Many sufferers develop leukemia as children or teen-agers, but they also are at risk for tumors of the brain, head and neck, breast, colon and other parts of the body. The disease afflicts about 500 families in the United States and 3,000 worldwide.

The Frohnmayers in 1989 founded the Eugene-based Fanconi Anemia Research Foundation, which contributed to this latest research through its funding and annual scientific meetings. The National Heart, Lung and Blood Institute, part of the National Institutes of Health, also funded the research.

The groundbreaking research was published Thursday in the journal Science. The article's authors are from the Dana-Farber Cancer Institute at Harvard Medical School in Boston; Oregon Health & Science University in Portland; Free University Medical Center in Amsterdam; and the Sapporo Medical University School of Medicine in Japan.

The central players in the study are genes called BRCA1 and BRCA2. Previous studies have indicated that these genes cause familial breast cancer as well as ovarian and pancreatic cancers. The research found the BRCA2 gene also is involved in the development of two forms of Fanconi anemia.

"We suspected that BRCA2 played an important role in Fanconi anemia because cells from FA patients and BRCA-mutated cells behaved so similarly," said Dr. Markus Grompe, a professor of molecular and medical genetics who led OHSU's research team.

Fanconi anemia is caused by a mutation in any of six genes in human cells. In recent years, researchers have mapped out the chain of events by which these genes are switched on.

When a cell's DNA is damaged, five of the Fanconi genes team up to produce a protein complex that stimulates a sixth gene, dubbed D2. The D2 gene orders production of a protein that moves near BRCA1, whose job is to help repair damaged DNA.

If BRCA1 or its partner in DNA repair, BRCA2, are defective or aren't switched on properly, DNA damage can accumulate in cells, increasing their chances of malfunctioning and becoming cancerous.

The proximity of the D2 protein to BRCA1 suggested, but didn't prove, that D2 activates BRCA1.

"It was a matter of guilt by association," said the study's lead author, Dr. Alan D'Andrea of the Dana-Farber Cancer Institute. "We knew they were in the same neighborhood, but we didn't know if one directly stimulated the other."

To test their theory, researchers drew blood samples from a small group of children who have Fanconi anemia but who don't have mutations in the six previously known Fanconi genes. They analyzed their cells for abnormalities in BRCA1 and BRCA2. They found that while the BRCA1 genes were normal, each patient had two flawed copies of BRCA2. This meant each parent carried a copy of a flawed BRCA2 gene and transferred the mutated gene to their child.

The finding proved that the chain of events, or pathway, that begins with the Fanconi anemia genes leads directly to BRCA1 and 2, which work together to repair damaged DNA. If BRCA1 or 2, or any of the Fanconi genes are defective, DNA repair is blocked, which can lead to cancer.

The research may allow doctors, as soon as six to 12 months from now, to run new tests that would determine if a patient is at risk for developing cancer, D'Andrea said. And it may encourage drug companies to develop new drugs capable of treating or preventing breast cancer by fixing errors in specific genes.

But OHSU's Grompe cautioned that such speculation is, for now, "science fiction."

For the Frohnmayers, whose foundation has been leading the lonely efforts to research Fanconi anemia, the research linking the disease to the mainstream of cancer research is exciting news.

Fanconi researchers will be able to take advantage of the work that the leading breast cancer researchers have developed, and vice versa, Lynn Frohnmayer said.

"More labs and more scientists will be focusing on the same issue," she said. "The capacity to figure out how to correct this (genetic) pathway we share with inherited breast cancer has grown by a huge multiplier effect."

"In terms of our research fund, it's the single most important development in several years," Dave Frohnmayer said. "The pieces of the puzzle are now coming together."

The Frohnmayers have another daughter, 15-year-old Amy, who shows early signs of the disease.

``She's doing very well in school, playing competitive tennis,'' he said, but ``she knows the score in this race against the clock.''

The Associated Press contributed to this report.

FANCONI ANEMIA

The disease causes bone marrow failure. Bone marrow slowly stops making red and white blood cells and platelets.

It's a recessive disorder, meaning that when both parents carry a defect in the same gene, there's a 1-in-4 chance their child will be born with it. Many FA patients develop acute myelogenous leukemia. Older patients may develop other cancers. The disease usually reveals itself from ages 3 to 12.

To learn more about Fanconi anemia, or to support research, contact the Fanconi Anemia Research Fund, 1801 Willamette St., Suite 200, Eugene 97401. Phone: [phone]. On the Web: www.fanconi.org.

- The Register-Guard

CAPTION(S):

Chromosomes from Fanconi anemia cells (left) and breast cancer cells (right) show fragmentation that indicates disease.