Genetic signature predicts recurrence of breast, prostate and other cancers, Stanford researchers find

STANFORD, Calif. - Researchers working with breast cancer stem cells at the Stanford University School of Medicine have found 186 genes that together can predict the risk of recurrence in breast cancer patients. Additionally, the same genes predict the recurrence of prostate cancer, lung cancer and medulloblastoma, the most common form of childhood brain cancer.

"These data suggest that there are some fundamental properties of the malignancy that are shared between many types of tumors," said Michael Clarke, MD, the Karel H. and Avice N. Beekhuis Professor in Cancer Biology. He is the lead author of the study, which is published in the Jan. 18 issue of the New England Journal of Medicine.

Clarke and his colleagues also found they could predict aggressive cancers with even greater accuracy when they combined the 186-gene signature with another previously identified group of genes in the cells surrounding the tumor.

Stanford scientists say the findings are a significant step toward using insights from cancer stem cell research to develop better tools for diagnosing and treating the disease.

"This paper demonstrates, for the first time, the clinical value of isolating pure human cancer stem cells," said Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Medicine, who was not involved in the study. "Mike Clarke and his colleagues have now shown that the human breast cancer stem cell reveals information not evident when the whole tumor is analyzed. We plan to incorporate these findings in our approaches to the care of cancer patients, starting here at Stanford."

Clarke has already begun working with surgeons to help translate these findings into tools that will help doctors zero in on the best treatment for individual cancer patients. For instance, he hopes that within five years a surgeon would be able to leave more breast tissue intact in a patient whose genetic profile showed that her tumor was unlikely to return. Likewise, a woman at high risk of relapse would get more aggressive treatment.

Frederick Dirbas, MD, an assistant professor of surgery at Stanford who was not involved in the study, said results such as these could have significant benefit to patients. "This work should lead to new opportunities for more accurate care of the individual patient," he said.

Cancer stem cells are believed to be the cells that continually replenish cancer, like the spring at the source of a creek. Although other cancer cells can damage the body through sheer bulk, they can't form new cancers.

Clarke found the first cancer stem cell in a solid tumor in 2003 while at the University of Michigan. Until he found the deadly cells in breast cancer, researchers had thought they might be restricted to blood cancers. Since then, other researchers have found the cells in brain and prostate cancer. Just this month Mark Prince, MD, an assistant professor at the University of Michigan, working with Stanford researchers including Clarke, Weissman and Laurie Ailles, PhD, reported finding cancer stem cells in head and neck cancers.

Clarke's newest breast cancer study isn't the first to identify a group of genes that can predict the risk of cancer recurrence. However, he said these genes are particularly effective at flagging risky cancers, especially when combined with a second group of genes originally identified by a team led by Patrick Brown, PhD, professor of biochemistry. These genes are active in the normal cells surrounding the tumor, called the stroma.

In essence, combining the two gene profiles is like examining both the soil (the stroma) and the seed (the cancer stem cells) to find out if the combination is likely to produce a tumor that can recur. Clarke said the finding shows that malignancy is the result of an interaction between the cancer cells in the tumor and the environment, as many researchers had previously surmised.

Although Clarke and his team identified the genetic pattern in breast cancer stem cells taken from tumors, they verified the results in a standard tumor biopsy containing a range of cell types. That same biopsy can also remove the stromal cells that are needed for the second genetic profile.

Over time, Clarke said, researchers will likely be able to refine the list of genes needed to most accurately determine a patient's risk of recurrence. A smaller list of genes could make a genetic profiling test more cost-effective for widespread use.

This work was supported by grants from the National Cancer Institute, the Breast Cancer Research Foundation and the Virginia and D.K. Ludwig Foundation.

Other Stanford researchers who contributed to this work include Piero Dalerba, MD, postdoctoral scholar, and Gavin Sherlock, PhD, assistant professor of genetics.



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