Alan D'Andrea, MD, searches for a genetic connection between a rare condition and a common cancer.
The hazards of cell disrepair
For the better part of a decade, Alan D'Andrea, MD, studied a rare condition called Fanconi anemia expecting to find a genetic connection to a common type of cancer. The question was, which type?
This year, when D'Andrea and his colleagues made the connection, they may have had a moment of disbelief: the gene they'd found a link to was none other than BRCA1, the most common source of inherited breast cancer. "It was a very exciting discovery," D'Andrea says. "That we made a connection, though, wasn't surprising."
Fanconi anemia is caused by a mutation in any of seven genes within human cells. Children who inherit one of those mutations usually develop bone marrow failure by age 5, leaving them unable to produce red blood cells. While a bone marrow transplant can cure that problem, many patients go on to develop cancer as young adults — usually leukemia, but also tumors of the brain, head and neck, esophagus, breast, or other parts of the body.
Working with fractions |
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Condition |
Estimated number of affected families worldwide |
||
Li-Fraumeni syndrome |
200 |
||
Fanconi anemia |
2,000 |
||
von Hippel-Lindau disease |
1,500 |
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The fact that Fanconi anemia patients often develop tumors suggested the genes responsible for the disease somehow subvert the process by which cells repair genetic damage and die at the end of their natural life span.
(Cancer cells are like demolition derby cars that take multiple "hits" yet refuse to die.) "The Fanconi genes could have been connected to any number of cancer-related genes — to p53, for example, which controls the normal process of cell death, or to other genes involved in the cell cycle, but they turned out to be linked to BRCA1, which most people know as the 'breast cancer gene,'" D'Andrea explains.
Under normal conditions, BRCA1 is the essence of beneficence. It is part of the molecular repair crew that mends damaged genes, ensuring that cells don't pass flawed DNA on to their offspring. When BRCA1 is defective, however, such repairs come to a halt, increasing the chances that cells will become cancerous.
For years, researchers have sought to find other genes that cooperate with BRCA1 in DNA repair. D'Andrea and his team found that one of those genes is FANCD2, a gene that itself is activated by a combination of five genes associated with Fanconi anemia. When all those genes are normal — as in the vast majority of the population — the process works smoothly: BRCA1 and FANCD2 cooperate in keeping genetic material error-free. When any of them, including FANCD2, are mutated, BRCA1 may be thwarted.
The discovery means that physicians may soon have a new tool for determining who is at risk for hereditary breast cancer or other inherited cancers. Women who have normal BRCA1 but abnormal Fanconi genes may have an inborn tendency to develop tumors in the breast or elsewhere.
People with Fanconi anemia are at high risk for leukemia, in which the body produces too many white blood cells.
For D'Andrea, studying a rare condition like Fanconi anemia — with an estimated 500 affected families in the U.S. — is doubly rewarding. "I've had the opportunity to get to know many Fanconi families very well," he says. "There's a personal satisfaction in helping them deal with a very serious disease. Part of my hope in studying Fanconi anemia is to cure people by developing novel diagnostic and therapeutic techniques.
"But I'm also interested in answering very fundamental questions about cell biology," D'Andrea adds. "I care about the basic mechanisms of how genes interact and proteins function to help cells grow and divide. What we study in my laboratory applies to normal cell growth as much as it does to cancer growth."
He notes that there's nothing contradictory about these dual interests. Indeed, the two sides reinforce each other. "I understand the science better because I understand many of the clinical aspects of Fanconi anemia. And I understand the clinical medicine better because I understand the science," he observes.
D'Andrea increasingly finds himself invited to speak at conferences of biochemists and cell biologists — basic researchers who may know nothing about the clinical effects of Fanconi anemia. His discovery of a link to BRCA1 also means he's collaborating more frequently with scientists who are studying breast cancer.
"It's an exciting time in science," D'Andrea remarks, "when two fields grow up independently, and a discovery is made that leads investigators in both groups to realize they're working on the same problem."
- Next: Seeking a cellular switch
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