The study’s findings, published December 5, 2011, in the journal Oncogene, provide new clues into the biology of a new class of cancer marker and suggest that a genetic test may help direct the treatment of women with ovarian cancer. “This gives us a way to identify which women are at highest risk for resistance to platinum chemotherapy, the standard treatment for ovarian cancer, and helps identify ovarian cancer patients with the worst outcomes,” said Dr. Joanne Weidhaas, associate professor of therapeutic radiology at Yale University (New Haven, CT, USA) and senior author of the study. “There just aren’t many inherited gene variants than can do that.”

Women who have the biomarker identified by the Yale scientists--a variant of the well-known KRAS [V-Ki-ras2 Kirsten rat sarcoma] oncogene--are three times more resistant to traditional platinum chemotherapy than women without the variant are. Moreover, postmenopausal women with the variant are considerably more likely to die from ovarian cancer. Approximately 12%-15% of Caucasians and 6% of African-Americans are born with the variant of the gene, which helps regulate destruction of damaged cells. This variant is found in up to 25% of newly diagnosed ovarian cancer patients.

Although good alternatives to chemotherapy are not yet available for women with ovarian cancer and this variant, several agents in development, which target the KRAS gene and associated pathways have shown great promise, according to Dr. Weidhaas. Dr. Weidhaas is a cofounder of a company that has licensed intellectual property from Yale that has developed a diagnostic test based on the Kras-variant.

The biomarker intrigues scientists because it is a functional variant in an area of DNA that does not code for proteins. Instead, this variant disrupts how a microRNA controls gene expression. “This is a new paradigm,” Dr. Weidhaas said.

Yale researchers have also discovered this microRNA variant of the KRAS gene is associated with an increased risk of developing breast cancer and lung cancer. Other researchers have found associations with poor outcome in colon as well as head and neck cancers.

In laboratory tests, researchers blocked the variant and considerably reduced growth of ovarian cancer cells. This suggests targeting the variant site may help in the future treat cancer in these patients.

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