A missing link found to breast cancer

For 10 years, Alan D’Andrea labored to find the cause of one of the rarest diseases on Earth. Called Fanconi anemia, it affects only 500 families out of 280 million people in the United States.

What kept him going, besides an inherent interest in the “orphan” disease, was the idea that such rare maladies sometimes provide key insights into common diseases that sicken and kill many thousands of people. Indeed, after years of research, D’Andrea and his colleagues discovered that a gene responsible for the anemia also plays a key role in inheritable breast cancer. A long, lonely trail toward an obscure destination had led them to a scientific pot of gold.

When everything works as it should, a Fanconi gene helps repair damage that otherwise dramatically raises the risk for many types of cancers, including breast cancer. When the gene is abnormal, genetic damage accumulates and tumors grow and spread.

The discovery may well lead to new tests to determine who is most at risk for inheritable breast cancer, which affects about 8,500 women each year in the United States alone. What is more, it could play a role in designing new treatments for 170,000-plus cases of noninheritable breast cancer.

A horrible disease

Children who inherit Fanconi are often born without thumbs. They are smaller than normal and sometimes have kidney problems. By age 5 or 6, victims develop anemia, that is, they lose the ability to make red blood cells. If they survive by transfusions or a bone marrow transplant, many of them develop cancer by age 10-15. Mostly it’s leukemia, but they also suffer from brain, neck, and esophageal tumors, as well as other types of cancers.

Cancer in his own family led D’Andrea to decide on a career in cancer biology while he was a student at Harvard University 23 years ago. “I didn’t know how to go about it, so I just rode my bicycle to the Dana-Farber Cancer Institute in Boston and looked around for a scientist I could work with,” he recalls.

At the time, researchers were beginning to sequence genes, and he decided to use this new technique to study DNA damage and how it leads to cancer. The senior thesis he wrote on the subject included a section on Fanconi anemia.

D’Andrea earned his M.D. degree from Harvard Medical School in 1983, and seven years later wound up as a new assistant professor at the Dana-Farber Cancer Institute, working down the hall from where he did his undergraduate research.

One day, David Frohnmayer, president of the University of Oregon and father of three children with Fanconi anemia, came to see him, along with his wife and a sick daughter. D’Andrea was so touched by the visit, he decided to work on the disease. Frohnmayer had started the Fanconi Anemia Research Fund, so he was able to provide some funds to help D’Andrea get started.

At the time, medical scientists believed the mutation of a single gene caused Fanconi. Children received one copy of the gene from both their mother and father, and that led to a chain of events that eventually killed them. Over succeeding years, however, D’Andrea and other researchers found five different genes that were involved in producing the deadly anemia.

Then, Markus Grompe of the Oregon Health Sciences University in Portland discovered a sixth gene. Grompe and D’Andrea got together and cloned, or made copies of it. When that gene, called Fanconi D, is activated, it produces small dots of material in the core, or nucleus, of the cell where it resides.

Those spots looked familiar. David Livingston, Emil Frei Professor of Medicine at Harvard, made a similar discovery related to a breast cancer gene, called BRCA1, in 1995. When mutated, BRCA1 is the major cause of inherited breast cancers, and it also produces small dark dots in the nucleus of cells that have DNA damage. (DNA is the material of which genes are made.)

Could the two sets of spots mean that the same kind of genetic damage is occurring? With the help of postdoctoral fellows Irene Garcia-Higuera and Toshiyasu Taniguchi, D’Andrea overlaid the spot sets. Sure enough, they matched.

“That was the eureka moment for us,” remembers D’Andrea, now a professor of pediatrics at Harvard Medical School and Ted Williams Senior Investigator at Dana-Farber. “The protein made by the Fanconi D gene must cooperate with the BRAC1 gene to repair damaged DNA in a cell. When this system functions normally, genetic errors are erased. When one of the genes goes awry, cancer results.”

As D’Andrea had hoped, a missing link had been found between a rare anemia and a cancer that sickens and kills thousands of women each year. “That was an exciting day in our laboratory,” he recalls.

More links in the chain

The chain that contains this missing link goes back further in the other direction. Five other genes are needed to switch on Fanconi D. If any of these genes are abnormal, a person gets the lethal anemia. If gene D does not get turned on, and the BRACI gene is abnormal, the person’s risk of cancer skyrockets.

This means that a test for mutations of Fanconi genes could aid in finding women with normal BRCA1 genes who are still at risk for breast cancer. If the Fanconi D gene is mutated for example, a good BRAC1 gene will not get turned on.

Faulty BRAC1s are responsible for only about 5 percent of breast cancers, or some 8,500 new cases a year. That’s many more people than suffer from Fanconi, but D’Andrea has his sights set on helping the other 95 percent of women threatened by breast cancer.

Those born with mutated Fanconi genes cannot dodge the lethal anemia and cancer. But suppose a person acquires a mutation in one of these genes via exposure to radiation, toxic pollutants, or some other environmental insult? “We want to test the tumors of people with noninherited breast cancer to determine if the Fanconi pathway is disrupted,” D’Andrea notes. “If it is, we might be able to make recommendations about the most effective type of treatment. For example, perhaps cancers in which acquired mutations have affected Fanconi genes are more treatable with certain drugs than are other cancers. On the other hand, such tumors may be more aggressive, more likely to spread.”

Such a scenario could extend the benefit of the Fanconi connection to thousands, even hundreds of thousands more women.

And there’s a possibility for a new type of breast cancer treatment. A drug might be found to accelerate BRCA1’s DNA repair circuit. If a woman has a strong predisposition to breast cancer because of a weakness in the Fanconi to BRAC1 link, it may be possible to design a drug to override the weakness and drastically reduce her risk of developing cancer.

“If that could be done, it would be really lucky,” comments D’Andrea, who has been really lucky so far.