Genetic Culprit: Mutation increases risk for uterine fibroids

Analysis of DNA from families whose women have been beset by uterine growths reveals a mutation that can predispose women to these so-called fibroids.

Uterine fibroids are common, benign tumors that can cause pain, pelvic pressure, infertility, and long, heavy periods in women of childbearing age.

Their cause has been unknown. Medication that slows estrogen production can ease symptoms but doesn’t cure the problem. Many women with severe symptoms undergo hysterectomies–removal of the uterus–making fibroids the most common reason for this surgery in the United States.

Using blood samples from families with a history of fibroids, researchers in Finland tracked genetic aberrations in some women to a region of DNA on chromosome 1. Meanwhile, researchers studying DNA from a separate set of families in Britain were also homing in on this chromosomal area. The teams pooled their efforts and report in an upcoming issue of Nature Genetics the discovery of mutations of the gene that encodes an enzyme called fumarate hydratase. Previous research had shown that this enzyme normally enables a cell to derive energy by metabolizing sugar.

If both parents pass on a mutated copy of the fumarate hydratase gene, the results are disastrous. The infant usually dies within months.

However, when only one of the parents provides a mutated copy, the child generally shows no abnormalities. If the other gene copy later becomes mutated in some cells, however, they can stop producing fumarate hydratase, says study coauthor Ian P.M. Tomlinson, a geneticist at the Imperial Cancer Research Fund in London. In the skin of both men and women, this loss can cause painful lumps, whereas in the uterus it can cause fibroids. Indeed, the researchers measured unusually low activity of fumarate hydratase in the fibroids in women with the mutated gene.

The conclusion that the mutation predisposes a woman to fibroid formation “is very plausible,” says Barbara J. Davis, a pathologist at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, N.C. The metabolic disruption could steer a cell onto an aberrant growth path.

However, many factors probably influence fibroid growth, she says. Uterine muscle cells, unlike other muscle cells, might be particularly vulnerable to growth abnormalities. In premenopausal women, the uterus is regulated in part by estrogen, a hormone broadly associated with cell growth, she says.

Uterine fibroids are common, says Donna Day Baird, an epidemiologist at NIEHS. In one study, she and her colleagues found that by age 50, more than 80 percent of black women and roughly 70 percent of white women developed uterine fibroids detectable by ultrasound.

The link between the fumarate hydratase gene mutation and uterine fibroids is clear but probably explains only a minority of cases, says study coauthor Lauri A. Aaltonen of the University of Helsinki.

Still, discovery of the mutations could help identify women at risk of fibroids, Tomlinson says, and might provide insight into how fibroids grow–information that scientists might use to block that growth.