Photo by Dean Forbes
In diverse ecosystems packed with wildly different species, evolution creeps along. As species accumulate mutations, some adapt well to their environment and prosper. It happens in marine sediments, mountain forests — and, as a new study illustrates, in precancerous tumors, too.
In a study published in the April issue of the journal Nature Genetics, former Hutchinson Center researcher Dr. Carlo Maley and his colleagues in the Human Biology Division report that precancerous tumors containing highly diverse cells are more likely to evolve into cancer than those containing genetically similar cells. The finding suggests that, at least in some forms of cancer, the more genetically diverse a precancerous tumor is, the more likely that tumor is to progress to full-blown cancer. If so, genetic diversity might act as a biomarker for cancer risk among patients with precancerous tissues.
"Although researchers first defined cancer in evolutionary terms in the 1970s, few researchers have actually studied the disease this way," said Maley, now an assistant professor in the molecular and cellular oncogenesis program at The Wistar Institute in Philadelphia. "We wanted to know if we measured a precancerous tumor's genetic diversity at baseline, could we predict who would go on to get cancer?"
Dr. Brian Reid, principal investigator of the Seattle Barrett's Esophagus Program, initiated the study with Maley when he worked in Reid's lab at the Center. He noted that many of the scientists who did the early, pioneering work in generating data leading to the evolutionary model of cancer that influenced the Barrett's study were at the University of Washington, including Drs. Phil Fialkow and Stan Gartler.
For this study, the scientists analyzed data on Barrett's esophagus, a precancerous condition in which cells lining the lower esophagus change due to repeated exposure to stomach acid from reflux, or heartburn. Doctors typically adopt a "wait and watch" approach to treating patients with Barrett's esophagus because the condition only rarely leads to cancer and is difficult to treat surgically.
Impacts of genetic diversity
Maley and Reid, along with Reid Lab colleagues Rissa Sanchez, Patricia Galipeau and Drs. Thomas Paulson, Patricia Blount and Peter Rabinovitch, as well as SCHARP's Dr. Xiaohong Li, looked at precancerous tumor data from 268 patients, including multiple biopsies within each tumor. On average, these patients were followed for almost four and a half years, during which time 37 developed cancerous tumors. Overall, the database used in the study represents more than 32,000 distinct genotypes of different cells within the tumors.
Using computational techniques to analyze the data, the scientists calculated measures of diversity inside the tumors. Essentially, they counted cell varieties and measured the genetic difference, or divergence, between those varieties. They found a striking correlation between increased diversity of tumor cells and progression to cancer. For every additional cell variety detected in a tumor, the patient was twice as likely to eventually get cancer.
The data suggests that genetically diverse tumors have a high probability of generating mutant cells that will flourish and spread, allowing the tumor to transform and grow. In the future, in addition to serving as a biomarker for cancer risk, measures of genetic diversity might help doctors assess the success of cancer-prevention therapies.
In fact, Maley believes genetic diversity among tumor cells might help explain why therapy sometimes fails. If a tumor contains a diverse population of cells, some of those cells are more likely to resist treatment, he said. Adapting to and surviving chemotherapy, these resistant cells could proliferate, leading to a cancer relapse. He hopes to pursue this hypothesis in the future. "More immediately, we intend to validate the new study with other cohorts and other types of tumors," he said.
"We view this as a very important collaboration between Carlo and our team here," Reid said. "We're going to continue to explore the evolutionary basis of cancer as a joint collaboration between The Wistar Institute and the Center."
Co-authors also include Drs. Jennifer Finley, Jon Wongsurawat and Rosana Risques of the University of Washington. The research was funded by the National Institutes of Health and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.