Tag Archives: Yale Cancer Ctr.

Yale Identifies KRAS Gene Variant in Ovarian Cancer Patients With “Non-BRCA” Family History of Breast/Ovarian Cancer

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A team of Yale researchers have identified a genetic marker that can help predict the risk of developing ovarian cancer, a hard to detect and often deadly form of cancer.

A team of Yale researchers have identified a genetic marker that can help predict the risk of developing ovarian cancer, a hard to detect and often deadly form of cancer.

Reporting online in the July 20 edition of the journal Cancer Research, the team showed that a variant of the KRAS oncogene [KRAS variant allele at rs61764370] was present in 25 percent of all ovarian cancer patients. In addition, this variant was found in 61 percent of ovarian cancer patients with a family history of breast and ovarian cancer, suggesting that this marker may be a new marker of ovarian cancer risk for these families, said the researchers.

Joanne B. Weidhaas, M.D., Associate Professor of Therapeutic Radiology & Researcher, Yale Cancer Center

Frank Slack, Ph.D., Professor of Molecular, Cellular & Developmental Biology, Yale University

“For many women out there with a strong family history of ovarian cancer who previously have had no identified genetic cause for their family’s disease; this might be it for them,” said Joanne B. Weidhaas, M.D., associate professor of therapeutic radiology, researcher for the Yale Cancer Center and co-senior author of the study. “Our findings support that the KRAS-variant is an new genetic marker of ovarian cancer risk.”

Weidhaas and co-senior author Frank Slack, also of Yale, first searched for the KRAS-variant among ovarian cancer patients and found that one in four had the gene variant, compared to 6 percent of the general population. To confirm that the KRAS-variant was a genetic marker of ovarian cancer risk, they studied women with ovarian cancer who also had evidence of a hereditary breast and ovarian cancer syndrome. All these women had strong family history of cancer, but only half in their study had known genetic markers of ovarian cancer risk, namely BRCA1 or BRCA2 mutations.

Six out of 10 women without other known genetic markers of ovarian cancer risk had the KRAS-variant. Unlike women with BRCA mutations who develop ovarian cancer at a younger age, women with the KRAS-variant tend to develop cancer after menopause. Because ovarian cancer is difficult to diagnose and thus usually found at advanced stages, finding new markers of increased ovarian cancer risk is critical, note the researchers.

Genetic tests for the KRAS-variant [PreOvar™] are currently being offered to ovarian cancer patients and to women with a family history of ovarian cancer by MiraDx, a New Haven-based biotechnology company that has licensed the Yale discoveries.

The study was funded by the National Institutes of Health. Weidhaas and Slack have a financial interest in MiraDX.

Other Yale authors of the paper include: Elena Ratner, Lingeng Lu, Marta Boeke, Rachel Barnett, Sunitha Nallur, Lena J. Chin, Cory Pelletier, Rachel Blitzblau, Renata Tassi, Trupti Paranjape, Herbert Yu, Harvey Risch, Thomas Rutherford, Peter Schwartz, Alessandro Santin, Ellen Matloff, Daniel Zelterman.

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Disarming Specialized Stem Cells Might Combat Ovarian Cancer

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Eliminating cancer stem cells (CSCs) within a tumor could hold the key to successful treatments for ovarian cancer, which has been notoriously difficult to detect and treat, according to new findings published this week in the journal Oncogene by Yale School of Medicine researchers.

Eliminating cancer stem cells (CSCs) within a tumor could hold the key to successful treatments for ovarian cancer, which has been notoriously difficult to detect and treat, according to new findings published this week in the journal Oncogene by Yale School of Medicine researchers.

“We found that stopping the expression of two genes—Lin28 and Oct4—reduces ovarian cancer cell growth and survival,” said Yingqun Huang, M.D., Ph.D., assistant professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Ovarian cancer is challenging to treat because it tends to recur frequently and develop resistance to treatment. The poor outcome for women with ovarian cancer is associated with subtle and nonspecific symptoms—earning it the moniker the “disease that whispers.”

“This recurrence and drug resistance may be due to the presence of CSCs within the tumors that have the capacity to reproduce and to differentiate into non-CSC tumor cells that repopulate the tumor mass,” said Huang, who is a member of Yale Stem Cell Center and Yale Cancer Center. “Eliminating these CSCs may be key to successful treatments.”

While in the process of studying the functions of stem cell proteins in human embryonic stem cells, Huang and her colleagues unexpectedly discovered that a sub-population of ovarian cancer cells express stem cell proteins Lin28 and Oct4. They also found that the two proteins appear to act together in ovarian cancer tissue cells to produce more advanced tumors. Inhibiting their combined expression led to a significant decrease in the growth and survival of cancer cells. A larger-scale ovarian cancer study is currently underway to confirm the significance of the findings.

Genetic researchers prevent genes from functioning — a process commonly referred to as “knocking down” the gene — by inserting small interfering RNA (siRNA) molecules into the cells. Next, the research team will examine the effect of siRNA in ovarian cancer cells in the lab, and test the technique on mice. If successful, human clinical trials would follow. Treatment on cancer patients could occur within 10 years, Huang said.

“We hope we will soon be able to apply this new information to improve outcomes, perhaps by developing better diagnostic markers and treatment strategies that may be useful in customizing treatment for ovarian cancer patients,” said Huang.

The study was supported by Connecticut Innovations, the Fannie E. Rippel Foundation and the National Cancer Institute.

Other Yale authors on the study included Nita Maihle, Ph.D., and Shuping Peng.

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