In a study published online today in Nature Genetics, Carlo Maley, Ph.D., a researcher at The Wistar Institute, and his colleagues report that precancerous tumors containing a population of highly diverse cells were more likely to evolve into cancer than those containing genetically similar cells. The finding suggests that, in at least 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," says Maley, lead author on the study and an assistant professor in the molecular and cellular oncogenesis program at Wistar. "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?"
To find out, the scientists decided to analyze data on a precancerous condition called Barrett's esophagus, in which cells lining the lower esophagus change due to repeated exposure to stomach acid from reflux, a condition often referred to as 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.
In the study, Maley and colleagues analyzed precancerous tumor data from 268 patients, including multiple biopsies within each tumor. On average, these patients were followed for 4.4 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 researchers calculated measures of diversity inside the tumors. Essentially, they counted cell varieties and measured the genetic difference, or divergence, between those varieties. "Simply put, we took ecology measures of species diversity and translated them into measures of cell diversity within tumors," Maley says. The 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 progress to cancer.
Maley 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, he adds, measures of genetic diversity might help doctors assess the success of cancer prevention therapies.
In fact, he speculates, 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, Maley says. Adapting to and surviving chemotherapy, these resistant cells could breed, leading to a cancer relapse. He hopes to pursue this hypothesis in the future. "More immediately," he adds, "we intend to validate the new study with other cohorts and other types of tumors."
Maley is lead author on the study, which was initiated when he was a staff scientist at Fred Hutchinson Cancer Research Center in Seattle, prior to his arrival at Wistar. The additional coauthors are Patricia C. Galipeau, Xiaohong Li, Carissa A. Sanchez, Thomas G. Paulson, Patricia L. Blount, Peter S. Rabinovitch and Brian J. Reid, all at Fred Hutchinson Cancer Research Center, and Jennifer C. Finley, V. Jon Wongsurawat, and Rosa-Ana Risques at the University of Washington. Blount, Rabinovitch, and Reid also have appointments at the University of Washington.
Support for the research was provided by the National Institutes of Health and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health. Support for Maley's ongoing research is also being provided by the McLean Contributionship.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases, including AIDS and influenza. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center focused on basic and translational research. Discoveries at Wistar have led to the creation of vaccines for such diseases as rabies, rubella, and rotavirus; significant insights into the mechanisms of skin, brain, breast, lung, and prostate cancers; and the development of monoclonal antibodies and other significant research technologies and tools. News releases from The Wistar Institute are available to reporters by direct e-mail upon request.
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