Women’s Health Research at Yale (WHRY) is funding a study to explain how well-known genetic mutations can lead to ovarian cancer.
“Ovarian cancer is of particular importance for women’s health as it is often diagnosed too late for effective therapeutic intervention,” said Ryan Jensen, the study’s lead researcher. “By identifying the molecular circuitry disrupted by loss of the tumor-suppressing protein known as BRCA2, we have the opportunity to expose vulnerabilities that can be selectively targeted or lead to novel biological clues to aid detection and vastly improve the standard of care for this unique population of women.”
As the recipient of this year’s Wendy U. and Thomas C. Naratil Pioneer Award, Jensen, associate professor of therapeutic radiology, is determining the molecular drivers that lead to ovarian tumors in women who have mutations in the gene that produces BRCA2. BRCA2 is a protein that repairs errors in the human genome ultimately responsible for preventing the development of cancer cells.
“The BRCA1 and BRCA2 proteins function like an auto-correct function in text messaging,” Jensen said. “When the genes that code for BRCA1/2 are mutated and fail to correct DNA damage, tumor-promoting genes can become permanently altered and genetic mistakes accumulate, eventually leading a cell down a path to becoming a cancer cell.”
Jensen will manipulate fallopian tube cells and cells from the surface of ovaries that have been identified as the potential origin of ovarian tumors to determine how the loss of BRCA2 proteins can influence this process. BRCA1/2 gene mutations also carry increased risk for cancer of the breast, pancreas, and prostate.
“The American Cancer Society estimates that 22,440 women in the United States will be diagnosed with ovarian cancer this year, and 14,080 women will die of the disease,” said Dr. Carolyn M. Mazure, director of WHRY. “This study will advance our understanding of how ovarian cancer develops and offer hope for the many women born with genetic mutations that carry an extremely high risk for this disease.”
Jensen has already created fallopian and ovarian surface cells in which he can turn the BRCA2 protein “on” and “off” like a switch. This experimental system will provide a powerful model to test his hypothesis that cells without the BRCA2 protein experience profound genomic instability, a cellular state in which mutations begin to accumulate throughout a person’s genome at an alarming rate.
In the absence of the BRCA2 protein, these mutations usually end up killing the cell. But in rare cases and possibly in specific cell types, such as fallopian cells, the cells somehow manage to survive. Jensen’s study is designed to understand at the molecular level how this could happen.
In 2010, Jensen was the lead author of a study published in the journal Nature announcing the successful purification of the BRCA2 gene’s protein, the culmination of a 15-year effort that provided the critical groundwork for understanding the effect of these mutations.
WHRY funded a two-year study in 2013 in which Jensen’s laboratory began purifying 10 of the most common BRCA2 mutations and conducting experiments to determine if the mutations affect the function of a purified, intact BRCA2 protein sample. As not all mutations lead to cancer, Jensen’s goal is to develop a test that can quickly and accurately determine whether particular mutations are harmful or not.
Since its inception, WHRY has awarded $5 million in annual seed grants that have gone on to generate more than $95 million in external funding.
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