Researchers Pinpoint Two Genes That Trigger Most Severe Form of Ovarian Cancer


Key Points

  • Interactions between two genes, ARID1A and PIK3CA, have shown that their interaction is a factor in ovarian cancer.
  • In a mouse model, concurrent inactivation of ARID1A and overactivation of PIK3CA resulted in ovarian clear cell carcinoma 100% of the time.
  • ARID1A and PIK3CA mutations led to the overproduction of interleukin-6, which is known to trigger inflammation.

Researchers at University of North Carolina School of Medicine have created the first mouse model of the most aggressive form of ovarian cancer and found a potential route to better treatments and much-needed diagnostic screens. Led by Terry Magnuson, PhD, the Sarah Graham Kenan Professor and Chair of the Department of Genetics, a team of UNC genetics researchers discovered how two genes interact to trigger ovarian clear cell carcinoma and then spur its development. Their findings have been published in Nature Communications.

“It’s an extremely aggressive model of the disease, which is how this form of ovarian cancer presents in women,” said Dr. Magnuson, who is also a member of the UNC Lineberger Comprehensive Cancer Center. Not all mouse models of human diseases provide accurate depictions of the human condition. Dr. Magnuson’s mouse model, though, is based on genetic mutations found in human cancer samples.

Coexistent Genetic Mutations

Mutations in two genes—ARID1A and PIK3CA—were previously unknown to cause cancer. “When ARID1A is less active than normal and PIK3CA is overactive,” Dr. 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.

The study was spearheaded by Ronald Chandler, PhD, a postdoctoral fellow in Dr. Magnuson’s laboratory. Dr. Chandler had been studying ARID1A, a tumor-suppressor gene, when results from cancer genome sequencing projects showed that the ARID1A gene was highly mutated in several types of tumors, including ovarian clear cell carcinoma. Dr. Chandler began researching the gene’s precise function in that disease and found that deleting it in mice did not cause tumor formation or tumor growth.

“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,” Dr. Chandler said. 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,” Dr. 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.”

Role of Interleukin-6

Dr. Magnuson’s team also found that ARID1A and PIK3CA mutations led to the overproduction of interleukin-6 (IL-6), a cytokine known to trigger inflammation. “We don’t know if inflammation causes ovarian clear cell carcinoma, but we do know it’s important for tumor cell growth,” Dr. Chandler said.

Dr. Magnuson added, “We think that IL-6 contributes to ovarian clear cell carcinoma and could lead to death.”

Dr. 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, Drs. 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,” Dr. 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.”

Dr. Magnuson is the corresponding author for the Nature Communications article.

This study was supported by the National Institutes of Health. Dr. Chandler was supported by a Postdoctoral Fellowship from the American Cancer Society and an Ann Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.