Six new genes are linked to inherited breast cancer

A decade of research into one of the world’s least-known diseases has resulted in the discovery of six genes linked to inherited breast cancer. Investigators at Dana-Farber Cancer Institute and Children’s Hospital – teaching affiliates of Harvard Medical School – 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 fourfold, 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 Professor of Pediatrics Alan D’Andrea, the study’s senior researcher. “Women and their doctors can then use the information in deciding how to keep that risk at a minimum.”

The finding may also spur development of new treatments capable of preventing or quelling breast cancer in women at risk for the disease. Results of the research will be published today (June 13) in the online edition of the journal Science.

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 it is leukemia, but also tumors of the brain, head and neck, breast, colon, and other parts of the body occur.

“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.

Proximity of the D2 protein to BRCA1 suggested, but didn’t prove, that D2 activates BRCA1. “It was a matter of guilt by association,” says D’Andrea. “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.

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,’” says D’Andrea. “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 explains.

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 co-authors are Niall G. Howlett and Toshiyasu Taniguchi, research fellows in pediatrics; Nicole Persky; Edward A. Fox, Dana-Farber Cancer Institute and Children’s Hospital; Susan Olson; Barbara Cox; 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.