In a study published online by the journal Science (www.sciencemag.org) on June 13, investigators at Dana-Farber Cancer Institute and Children's Hospital Boston report that an error in any of the half-dozen genes involved in Fanconi anemia - a rare childhood condition - can increase an individual's chances of developing breast cancer. The discovery raises the prospect that the ranks of known breast cancer-susceptibility genes - best known as BRCA1 and BRCA2 - will soon increase four-fold, to a total of eight.
"Just as women today can be tested for BRCA1 and BRCA2 mutations to determine if they have an inherited predisposition for breast cancer, testing for mutations in these other six genes may soon become a routine part of gauging inherited breast cancer risk," says the study's senior author, Alan D'Andrea, MD, of Dana-Farber. "Women and their doctors can then use the information in deciding how to keep that risk at a minimum."
The finding may also spur the development of new treatments capable of preventing or quelling breast cancer in women at risk for the disease. Drugs that can counteract the flaws in specific genes promise to be more effective than therapies that take a more generic approach.
The discovery of the new cancer-susceptibility genes grew out of more than 10 years of research by D'Andrea into Fanconi anemia, a condition known to affect only 500 families in the United States. Children born with the condition usually develop bone marrow failure early in life, leaving them unable to produce oxygen-carrying red blood cells. If they survive into young adulthood - often with the help of a bone marrow transplant - they're at risk for a variety of cancers - most often leukemia, but also tumors of the brain, head and neck, breast, colon, and other parts of the body.
"This work is a prime example of how research into rare conditions can lead to better diagnosis and treatment for people with far more common diseases," D'Andrea explains.
Fanconi anemia is caused by a mutation in any of six genes in human cells. In recent years, D'Andrea and other investigators have mapped out the chain of events by which these genes are switched on. When a cell's DNA is damaged - whether by excessive sunlight, chemicals such as those found in cigarette smoke, radiation, or other means - five of the Fanconi genes team up to produce a protein "complex" that stimulates a sixth gene. That gene, dubbed D2, 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,'" D'Andrea remarks. "We knew they were in the same neighborhood, but we didn't know if one directly stimulated the other."
To find out, D'Andrea and his colleagues turned their attention to a small group of children who have Fanconi anemia but don't have mutations in the six Fanconi genes. They drew blood samples from them and 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 that each parent carried a copy of a flawed BRCA2 gene and had 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, the sequence of events is disrupted and DNA repair is blocked.
"You can think of the pathway as a fancy billiard shot," remarks D'Andrea, who is also a Professor of Pediatrics at Harvard Medical School. "Just as each billiard ball must strike the next one at the right speed and angle, each gene in the pathway must be activated in the proper sequence. A problem anywhere along the line can stymie the entire process."
D'Andrea describes two "eureka" moments when the connection between Fanconi anemia genes and breast cancer genes became especially tantalizing. Scientists have long known that breast cancer cells have a characteristic type of breakage in their chromosomes. D'Andrea speculated that cells from Fanconi anemia patients might have the same type of breakage. As a test, he gave a sample of breast cancer cells to a specialist in cell genetics and, without telling her what type of cell they were, asked her to analyze them for chromosomal abnormalities. "She came back and said, 'This patient has Fanconi anemia,'" D'Andrea relates. "The chromosomal similarities between Fanconi cells and breast cancer cells are so great that even someone with a trained eye cannot tell them apart."
The second moment was, in a sense, the reverse of the first. D'Andrea provided a sample of Fanconi anemia cells to a lab that analyzed their genetic characteristics. "The lab director called back and said, 'These samples must be mislabeled. They're breast cancer cells,'" D'Andrea remarks.
Now that the link between mutations for Fanconi anemia and breast cancer has been established, doctors may soon be able to offer new tests for determining who is at risk for inherited breast cancer, and potentially develop new drugs targeted at specific, flawed genes.
The paper's coauthors are Niall G. Howlett, Toshiyasu Taniguchi, Nicole Persky, and Edward A. Fox, Dana-Farber and Children's Hospital Boston; Susan Olson, Barbara Cox, and Markus Grompe, Oregon Health Sciences University, Portland; Quinten Waisfisz, Hans Joenje and Gerard Pals, Free University Medical Center, Amsterdam, The Netherlands; Christine de Die-Smulders, Academic Hospital Maastricht, The Netherlands; and Hideyuki Ikeda, Sapporo Medical University School of Medicine, Japan.
The study was supported by the National Institutes of Health and the Fanconi Anemia Research Fund.
Dana-Farber Cancer Institute (www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
Dana-Farber/Children's Hospital Boston Cancer Care is an integrated pediatric oncology program committed to providing a seamless patient care experience across the continuum of cancer care and support.