Two genes that trigger most severe form of ovarian cancer are pinpointed

Two genes that trigger most severe form of ovarian cancer are pinpointed
Two genes that trigger most severe form of ovarian cancer are pinpointed

In the battle against ovarian cancer, researchers have created the first mouse model of the worst form of the disease and found a potential route to better treatments and much-needed diagnostic screens. Their study was published in Nature Communications (2015; doi:10.1038/ncomms7118).

The genetics researchers discovered how two genes interact to trigger cancer and then spur on its development.

"It's an extremely aggressive model of the disease, which is how this form of ovarian cancer presents in women," said study leader Terry Magnuson, PhD, who is the Sarah Graham Kenan Professor and chair of the department of genetics at the University of North Carolina School of Medicine in Chapel Hill and a member of the UNC Lineberger Comprehensive Cancer Center.

Not all mouse models of human diseases provide accurate depictions of the human condition. Magnuson's mouse model, though, is based on genetic mutations found in human cancer samples.

Mutations in two genes, ARID1A and PIK3CA, were previously unknown to cause cancer.

"When ARID1A is less active than normal and PIK3CA is overactive," Magnuson said, "the result is ovarian clear cell carcinoma 100% of the time in our model."

The research also showed that a drug called BKM120, which suppresses PI3 kinases, directly inhibited tumor growth and significantly prolonged the lives of mice. The drug is currently being tested in human clinical trials for other forms of cancer.

"We found that the mice needed an additional mutation in the PIK3CA gene, which acts like a catalyst of a cellular pathway important for cell growth," said postdoctoral fellow Ron Chandler, PhD.

Proper cell cycle regulation is crucial for normal cell growth. When it goes awry, cells can turn cancerous.

"Our research shows why we see mutations of both ARID1A and PIK3CA in various cancers, such as endometrial and gastric cancers," Chandler said. "Too little expression of ARID1A and too much expression of PIK3CA is the perfect storm; the mice always get ovarian clear cell carcinoma. This pair of genes is really important for tumorigenesis."

Magnuson's team also found that ARID1A and PIK3CA mutations led to the overproduction of Interleukin-6 (IL-6), which is a cytokine, a kind of protein crucial for cell signaling that triggers inflammation.

"We don't know if inflammation causes ovarian clear cell carcinoma, but we do know it's important for tumor cell growth," Chandler said.

Magnuson added, "We think that IL-6 contributes to ovarian clear cell carcinoma and could lead to death. You really don't want this cytokine circulating in your body."

Magnuson added that treating tumor cells with an IL-6 antibody suppressed cell growth, which is why reducing IL-6 levels could help patients.

Although this research is necessary to find better cancer treatments, Magnuson and Chandler say that their finding could open the door to better screening tools.

"If we can find something measurable that's downstream of ARID1A, such as a cell surface protein or something else we could tease apart, then we could use it as a biomarker of disease," Chandler said. "We could create a way to screen women. Right now, by the time women find out they have ovarian clear cell carcinoma, it's usually too late. If we can find it earlier, we'll have much better luck successfully treating patients."

Loading links....
You must be a registered member of ONA to post a comment.

Sign Up for Free e-newsletters

Regimen and Drug Listings


Bone Cancer Regimens Drugs
Brain Cancer Regimens Drugs
Breast Cancer Regimens Drugs
Endocrine Cancer Regimens Drugs
Gastrointestinal Cancer Regimens Drugs
Genitourinary Cancer Regimens Drugs
Gynecologic Cancer Regimens Drugs
Head and Neck Cancer Regimens Drugs
Hematologic Cancer Regimens Drugs
Lung Cancer Regimens Drugs
Other Cancers Regimens
Rare Cancers Regimens
Skin Cancer Regimens Drugs