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Research Into Rare Disease Leads To Discovery Of Six New Breast Cancer-Susceptibility Genes

Date:
June 14, 2002
Source:
Dana-Farber Cancer Institute
Summary:
A decade of research into one of the world's least-known diseases has resulted in a major advance against one of the best-known: the discovery of six genes linked to inherited breast cancer.
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BOSTON – A decade of research into one of the world's least-known diseases has resulted in a major advance against one of the best-known: the discovery of six genes linked to inherited breast cancer.

In a study published online by the journal Science 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 Har


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Materials provided by Dana-Farber Cancer Institute. Note: Content may be edited for style and length.


Cite This Page:

Dana-Farber Cancer Institute. "Research Into Rare Disease Leads To Discovery Of Six New Breast Cancer-Susceptibility Genes." ScienceDaily. ScienceDaily, 14 June 2002. <www.sciencedaily.com/releases/2002/06/020614080810.htm>.
Dana-Farber Cancer Institute. (2002, June 14). Research Into Rare Disease Leads To Discovery Of Six New Breast Cancer-Susceptibility Genes. ScienceDaily. Retrieved March 27, 2024 from www.sciencedaily.com/releases/2002/06/020614080810.htm
Dana-Farber Cancer Institute. "Research Into Rare Disease Leads To Discovery Of Six New Breast Cancer-Susceptibility Genes." ScienceDaily. www.sciencedaily.com/releases/2002/06/020614080810.htm (accessed March 27, 2024).

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