Finding may help in screening women with endometriosis for cancer risk
Mutations in a gene called ARID1A may be responsible for some cases of ovarian cancer, two studies released September 8 show. The findings establish that the gene normally has a tumor-suppressing role, researchers report in Science and the New England Journal of Medicine.
The findings also improve the outlook for treating and screening ovarian clear-cell carcinoma, which comprises up to 10 percent of ovarian cancers, says David Huntsman, a pathologist and cancer geneticist at the University of British Columbia in Vancouver, Canada.
“Ovarian cancer management was a bit of a quagmire until recently, largely because people were treating it as a single disease,” he says. “It’s not.”
Ovarian cancer is stealthy. Only one in five cases is caught before the cancer has spread beyond the ovaries. Ovarian clear-cell carcinoma is a particularly aggressive form that responds poorly to treatment and can recur.
Writing in NEJM, Huntsman and colleagues report finding mutated ARID1A genes in 55 of 119 ovarian clear-cell tumors but in none of 76 ovarian tumors of a more common type called high-grade serous carcinoma. The researchers also tested 33 tumors of the uterine lining, called endometrial tumors, and found that ARID1A was mutated in 10 of them.
In a separate test, the researchers analyzed tissues from two patients who had both ovarian clear-cell cancer and endometriosis, a condition in which endometrial tissue grows outside the uterus, often on the ovaries. The scientists found that in both women, the ARID1A gene was mutated in ovarian tumors and nearby precancerous endometrial tissue, and the precancerous tissues failed to produce the protein normally encoded by ARID1A. Healthy endometrial tissue didn’t show these aberrations.
“This suggests that this [mutation] is a very early event in this cancer,” says Huntsman. “It’s possible that this [form of ovarian] cancer comes from cells that originate in the uterus.” This knowledge may someday be used to develop a test to determine which women with endometriosis are at risk of developing cancer, he says.
In the Science study, researchers at Johns Hopkins University in Baltimore report that ARID1A was mutated in 24 of 42 ovarian clear-cell carcinomas examined. Another gene, called PPP2R1A, was mutated in three of the tumors.
ARID1A normally encodes a protein called BAF250a, part of a complex in the cell’s nucleus called chromatin. This complex surrounds DNA and regulates which genes are switched on or off. To do this, chromatin is constantly remodeled in accordance with the needs of the cell. BAF250a normally contributes to chromatin remodeling, but when ARID1A is mutated, the cell fails to make usable BAF250a. As a result, chromatin remodeling is altered, and genes can get switched on or off inappropriately.
The mechanism by which those errors in gene regulation enable endometriosis to progress to cancer remains unknown, Huntsman says.
But there is no question that without the mutations, ARID1A inhibits cancer by producing functional BAF250a protein. “This is a tumor suppressor gene,” says Nickolas Papadopoulos, a cancer geneticist at Johns Hopkins University in Baltimore, who worked on the study in Science.
The findings will help to guide ovarian cancer research and ultimately treatment, says Elizabeth Moran, a molecular biologist at the University of Medicine and Dentistry of New Jersey in Newark. “The more we can separate people into different groups by cancer type,” she says, “the better the chances you have of choosing the right therapy — be it surgery, chemotherapy or radiation.”
K.C. Wiegand, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. New England Journal of Medicine, in press, 2010.
S. Jones et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science, in press, 2010.
X. Wang et al. Expression of p270 (ARID1A), a component of human SWEI-SNF complexes, in human tumors. International Journal of Cancer, Vol. 112, 2004, p.636.
D. Pectasides et al. Treatment Issues in Clear Cell Carcinoma of the Ovary: A Different Entity?The Oncologist, Vol. 11, November 2006, p.1089-1094. doi:10.1634/theoncologist.11-10-1089
K-T Kuo et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. American Journal of Pathology, Vol. 174, 2009, p. 1597-1601. doi: 10.2353/ajpath.2009.081000