On a recurring basis, a Yale oncologist will ask Dr. Ryan Jensen for help in interpreting a patient’s genetic screening results involving the breast cancer susceptibility mutations in BRCA1 and BRCA2 genes. Testing for these genetic mutations has become common clinical practice. But as Jensen knows, having devoted much of his health research career to studying the intricacies of the BRCA2 gene, providing clear answers about breast cancer risk based on genetic testing can be problematic.
Some BRCA mutations are known to be harmful, accounting for approximately 1 in every 10 breast cancer cases. About 45 percent of women who have a deleterious BRCA2 mutation, in fact, will develop breast cancer in their lifetime, compared to about 12 percent of women in the general population, according to the National Cancer Institute. BRCA2 mutations also carry a 30 percent increased risk for ovarian cancer.
However, the majority of the thousands of genetic variations identified in patients’ screening tests have not been characterized as being either harmful or innocuous, according to Jensen, Assistant Professor of Therapeutic Radiology and Pathology.
This ambiguity in genetic screening poses a very serious challenge in women’s health, as the standard of care for many patients with BRCA mutations known to increase cancer risk involves preventive double mastectomy, and removal of the ovaries and fallopian tubes. Atypical but unclear screening results often end in frustration for genetic counselors and health care providers and, more importantly, anxiety for the patients who do not have clear findings.
DISTINGUISHING BETWEEN HIGH RISK AND HARMLESS VARIANTS
This is where our Center’s mission to jump-start important women’s health research is playing its vital role. Jensen is using a WHRY Pilot Project Program grant to ignite development of a rapid laboratory test to discriminate between high risk and harmless mutations of the BRCA genes.
“We need to understand what all these mutations are, what they mean in terms of risk,” Jensen said. “I’m trying to reduce the confusion.”
He readily acknowledges that his project will take time — at least 6 years and probably several more — to accomplish and will require further funding, for example, from the National Institutes of Health, which supports breast cancer research. Clearly a high-risk endeavor, his project has the potential for high reward. Success in creating a method to stratify a patient’s risk based on genetic test results will be invaluable in guiding treatment decisions.
The current ambiguity that arises with genetic screening stems from the fact that scientists do not yet know enough about how cancer develops when BRCA genes carry mutations or how normal BRCA genes operate.
The protein synthesized by the BRCA2 gene is actually a tumor suppressor, signaling and initiating the repair of damaged DNA (deoxyribonucleic acid). This kind of reparative process occurs thousands of times a day as cells divide. DNA damage increases with age and, as Jensen explained, is the result of metabolic byproducts that can harm DNA. This damage also can occur when people are exposed to natural or medical radiation, or environmental toxins.
THE IMPORTANCE OF DNA REPAIR
In the absence of normal BRCA2 proteins, DNA repair can go awry. The mistakes or mutations can lead to cancerous cells and tumors.
Jensen’s experience studying cancer biology and, specifically, the workings of the BRCA2 gene place him in a small pool of scientists who can increase our understanding of these processes.
After graduating from the University of California at Berkeley with a B.A. in molecular and cell biology, Jensen worked at a San Francisco Bay Area drug discovery company that pioneered and developed a genetics-based cancer treatment that combats the disease by retarding both tumor growth and blood supply to tumors.
Next, he worked at Stanford Medical School’s Cancer Biology Research Laboratory and was well into his DNA repair studies when he arrived at Yale as a graduate student in 1999. He then led a study on enhancing the tumor-killing effects of a commonly used cancer chemotherapy drug, cisplatin. Dr. Jensen earned his Ph.D. in genetics from Yale in 2004 and did post-doctoral work at the University of California at Davis, where he continued to study DNA repair and played an instrumental role in a UC Davis/Yale team’s much heralded scientific feat involving BRCA2.
This breakthrough, published in 2010 in the prestigious journal Nature, was the “purification” or isolation of a pure extract of the tumor suppressor protein BRCA2 from human cells, in a test tube. The task took almost 15 years and was difficult because BRCA2 is a very large protein, consisting of more than 3,400 amino acids, is extremely unstable, exists in complexes with other proteins, and is tough to detect due to the low levels that exist in human cells.
Jensen, the first author on the study, spent six years of his career on this achievement, including four years optimizing the purification process. But it was worth the wait.
In simple terms, isolating the BRCA2 protein opened the door to studying its unique structure and function, and, most importantly, gaining understanding of how BRCA2 mutations cause cancer. (The BRCA1 protein is yet to be purified.)
Jensen’s previous accomplishment, in fact, made possible his current WHRY-funded investigation. Specifically, he is purifying approximately 10 of the most common BRCA2 mutations known to exist in the population, based on a data base of breast cancer mutations called the Breast Cancer Information Core, sponsored by the National Institutes of Health. In test tubes, he is incorporating each of these genetic variations into the BRCA2 protein purified from human cells. He will then conduct a battery of biochemical experiments to determine how these variations affect the function of the protein — including whether it is still able to repair normal DNA breaks.
To validate his approach, Jensen will incorporate variations that are already known to be either harmful or innocuous into the full protein in the test tube experiments, and will compare the results of these experiments with previously reported data on outcomes involving the same known variations.
Using this new method, Jensen plans to analyze many of the variations cataloged in the Breast Cancer Information Core data base that have yet to be characterized for their cancer risk.
Jensen ultimately plans to develop a test to determine the DNA repair status of individual patients’ tumors. With this knowledge, a health care provider will select an appropriate therapy for a specific patient’s tumor type.
“We’re really trying to tackle why DNA repair fails, and why tumors get started and evolve. BRCA2 is our model for understanding this,” he said. “Way down the road, we would like to come up with ways to prevent the tumor from evolving. But all of this depends on a fundamental understanding of DNA repair.”
TERMINOLOGY & DEFINITIONS
BRCA1 AND BRCA2
BRCA1 and BRCA2 are human genes responsible for producing proteins that suppress tumor growth.
DNA MUTATIONS
DNA is the material within the cell that tells it how to function. Mutations to the DNA can be inherited from a parent, acquired from environmental factors, or occur in the process of ongoing DNA repair.
DNA REPAIR
In the normal course of life, our cells divide, DNA breaks down and is repaired. In the absence of normal BRCA proteins, DNA repair can result in mutations that increase cancer risk.
PURIFYING BRCA2
Isolating a pure extract of the tumor suppressor protein in the BRCA2 gene allows us to understand its structure and function.
PURIFYING BRCA2 MUTATIONS
Isolating these mutations allows us to test which of these variations is associated with increased risk of cancer and which are not.
ABOUT THE INVESTIGATOR — Dr. Ryan Jensen earned his Ph.D. from Yale University. He is an Assistant Professor of Therapeutic Radiology and of Pathology. His research focuses on DNA repair and how repairs to this basic hereditary material go awry, leading to the initiation of tumors and cancer. A major focus of his work is to understand the role deleterious BRCA2 mutations play in increasing the risk for breast, ovarian and other types of cancer.
The Women’s Health Research at Yale Pilot Project Program is supported in part by the Maximilian E. and Marion O. Hoffman Foundation, the Seymour L. Lustman Memorial Fund, The Seedlings Foundation, The Werth Family Foundation, and anonymous donors.