Feb. 16, 2001 Boston - Scientists following the gene trail of one of the world's rarest diseases have found it leads to an entirely unexpected place - to BRCA1, a gene that, when defective, is the most common source of inherited breast cancer.
In two studies published in the February issue of Molecular Cell, researchers led by Alan D'Andrea, M.D., of Dana-Farber Cancer Institute show how genes involved in a condition called Fanconi anemia form a "pathway" to the activation of BRCA1. If BRCA1 or any of the Fanconi genes are abnormal, the risk of cancer increases dramatically.
"There's strong evidence that under normal conditions, BRCA1 helps repair DNA damage in cells, preventing the cells from becoming cancerous," D'Andrea says. "But until now, little was known of how BRCA1 is switched on. This new study presents a pathway leading to BRCA1 activation - and it was discovered by studying a condition that's known to affect only 500 families in the United States."
The finding means that physicians may soon have a new tool for determining who is at risk for inherited breast cancer. Since a mutation in any of the Fanconi genes can block BRCA1 from being activated - thereby preventing it from doing its DNA repair work - testing for those mutations may offer a way of identifying women likely to develop breast tumors.
Although inherited forms of breast cancer comprise only about 5 percent of all breast cancer cases, testing for mutations in Fanconi genes could help identify women with normal BRCA1 genes who are still at risk for the disease.
The new study is an outgrowth of D'Andrea's research into Fanconi anemia, an inherited disorder that causes children to develop bone marrow failure by age five, leaving them unable to produce oxygen-carrying red blood cells. While a bone marrow transplant can cure the failure, many patients go on to develop cancer as young adults - usually leukemia, but also tumors of the brain, head and neck, esophagus, or other organs.
The disease is caused by a mutation in any of seven genes within human cells. In previous research, D'Andrea and his colleagues showed that proteins produced from five of those genes form an enzyme that activates a sixth gene. In their first paper in this week's Molecular Cell, research teams led by D'Andrea and Markus Grompe, M.D., Ph.D., of Oregon Health Sciences University in Portland, Ore., report that they have identified and cloned that sixth gene, dubbed FANCD2. In the second paper, the groups demonstrate that, once activated, FANCD2 gives rise to a protein that switches on BRCA1.
"FANCD2 turns out to be the missing link between the Fanconi anemia enzyme and the switching on of BRCA1," D'Andrea says. "When FANCD2 is activated, it serves as a 'zip code' that sends the FANCD2 protein to BRCA1. Once bound, the FANCD2 and BRCA1 proteins cooperate in DNA repair."
When all the Fanconi genes and BRCA1 are normal - as in the vast majority of the population - the result of this chain of events is the repair of damaged DNA within cells. When any of those genes in the pathway are flawed, BRCA1 is not activated, causing genetic damage to build up in cells and setting the stage for cancer.
While the discovery may lead to new tests for determining who is at risk for inherited breast cancer, it could result in new therapies as well. "It might be possible to design a drug that amplifies this pathway, accelerating the repair work of BRCA1 and reducing the chances that breast cancer will occur in people with a genetic risk for it," D'Andrea says. "Much work, however, remains to be done before such therapies become a reality."
The study comes after a year in which D'Andrea has reaped several honors for his work. In the past 12 months, he has been promoted to full professor at Harvard Medical School, was named the Ted Williams Senior Investigator at Dana-Farber, received a Distinguished Clinical Scientist Award from the Doris Duke Foundation, and won the E. Mead Johnson Award for 2001.
Dana-Farber Cancer Institute (http://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), a designated comprehensive cancer center by the National Cancer Institute.
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