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Unraveling Ovarian Cancer

Cancer experts join forces—and travel to Africa—in a new study of one of the world’s most deadly cancers

By comparing the genetic makeup of ovarian tumors from two very different groups of women, researchers hope to discover what irregularities in DNA are shared because that could point to the cause of this deadly disease.

Ovarian cancer is among the deadliest of cancers, with less than 45 percent of women surviving five years after their diagnosis. It is more common in westernized countries than in developing countries, due in part to differences in childbearing patterns. But while studying data, Norris Cotton Cancer Center (NCCC) researcher Jennifer A. Doherty MS, PhD noticed a surprising statistic: women in Uganda (east Africa) and the United States have almost identical rates of ovarian cancer and mortality, despite completely different fertility rates—on average, women in Uganda have over six pregnancies while women in the U.S. have less than two. Why would ovarian cancer occurrence and mortality rates be so similar in women with such different genetic backgrounds and lifestyles?

"In the past few decades there has been little improvement in survival rates for ovarian cancer, which usually is detected at an advanced stage with little chance for cure. The ovarian cancer research community is working hard to find ways to improve therapies, but the difficulty lies in the complexity of the ovarian tumors themselves" said Doherty, assistant professor of Community & Family Medicine in Epidemiology at the Geisel School of Medicine at Dartmouth. "If we compared tumor characteristics in women with very diverse genetic backgrounds and lifestyle exposures, could the features shared by both groups represent the most important genes and pathways driving ovarian tumors? If so, that would dramatically reduce the complexity of the problem."

Uganda cancer

NCCC researchers Casey S. Greene PhD (3rd from left); Jennifer A. Doherty MS, PhD (4th from left); Laura Tafe, MD (5th from left); and Evelyn Fleming, MD (7th from left), traveled to Uganda to work with colleagues from the Uganda Cancer Research Institute and the Fred Hutchinson Cancer Research Center.

Unfortunately, existing studies of ovarian cancer to date include very few women who are not of European ancestry, so this would not be easy for Doherty to test. Building on an existing collaboration between the Uganda Cancer Research Institute and the Fred Hutchinson Cancer Research Center, she was inspired to take on this challenge. She recognized that she would need a multidisciplinary team—one that could approach the problem in new ways.

Experts in many areas of cancer research work together to study ovarian cancer

Doherty partnered with colleagues at NCCC: Casey S. Greene, PhD (genetics and bioinformatics); Laura Tafe, MD, (pathology); and Evelyn Fleming, MD (gynecologic oncologist), who each lead different aspects of their combined research. They traveled together to Uganda last fall to meet with their counterparts at the Uganda Cancer Institute and to immerse themselves in shaping their research.

New approach to studying ovarian cancer draws on cutting edge knowledge

"One of best things about our trip was that, in the absence of cell phones and Internet access, we were able to spend a lot of time talking with one another and learning about how our different skill sets can interact in ways that we had never imagined," said Tafe. "In fact, the discussions we had in Uganda sparked ideas for expanding our research that we are actively pursuing."

Like breast cancer, ovarian cancer is not one disease but a range of diverse tumor types. Of the five types of ovarian cancer, one of them—high grade serous—is responsible for 75 percent of ovarian cancer occurrence and 90 percent of ovarian cancer mortality. Recently, the discovery that this group itself has molecular subtypes has been met with considerable excitement, but much more research is needed to decipher what the key features are that characterize the subtypes. The hope is that treatments that target these subtypes can be developed, and may be more effective than broader therapies.

"There are so many changes in ovarian cancer, it is hard to know which ones are causing the tumor to be more aggressive, and which ones are just tagging along," said Doherty. "Little is known about tumors of Ugandan women, and we wondered: do their tumors fall into these known subtypes?"

Multidisciplinary teamwork to assemble data on Ugandan women with ovarian cancer

Working with researchers and physicians at the Ugandan Cancer Institute, Doherty's team is enrolling patients with ovarian cancer, who share details about their reproductive and medical histories, and provide blood and tumor samples for the study. Their samples are frozen and sent to NCCC, where Greene and other researchers will classify the tumors into subtypes by conducting RNA sequencing.

The final step will be to use newly developed bioinformatics methods from Greene's lab to compare the Ugandan data with that collected on Caucasian women to identify shared molecular features. Doherty and her team think these shared features could identify key genetic drivers and pathways for ovarian cancer, information that will help researchers zero in on areas to target for new treatments.

A novel approach to looking at data

"This is a new way to think about these types of problems. When looking for trends, we usually try to start by putting together the most similar data," said Greene. "Here we started by looking at two very different population groups to pull out common themes."

Doherty thinks that this multi-disciplinary team of cancer researchers using cutting edge technology in unconventional ways may help to unravel the complexity of ovarian cancer. It's an approach that could, in addition to identifying targets for treatment, advance future efforts at prevention, help to tailor clinical trials, and be applied to a wide range of other disease types.

Partners in this study, "Searching for Common Drivers of Molecular Subtypes of Ovarian Cancer across Diverse Populations," are: Jennifer Anne Doherty, MS PhD; Casey S. Greene, PhD; Laura Tafe, MD; Evelyn Fleming, MD; Jason Moore, PhD; Scott Williams, PhD; Christopher Amos, PhD; Jackson Orem, MD; and Corey Casper, MD, MPH. The research has been funded in part by grants from the Prouty Pilot program, Hitchcock Foundation, the American Cancer Society, and the Institute for Quantitative Biomedical Sciences.

May 13, 2014