Mayo Clinic Researchers Among First in the World to Discover Possible Early Gene Involved in the Development of Cancer

Tuesday, March 04, 2003

Mayo Clinic is one of three research laboratories around the world to independently discover that a gene named MDC1 appears to play a pivotal role in the development of cancers — including breast cancer.

The Mayo Clinic finding is significant because the MDC1 gene appears to be closer than most others investigated so far to the earliest events that go wrong in a healthy body and cause cells to turn cancerous. Specifically, MDC1 is a "checkpoint protein" that appears to guard against abnormal cells reproducing themselves, a process that leads to cancers.

The Mayo Clinic results — along with those from the other laboratories in Cambridge, England, and Baylor College of Medicine, Houston, Texas — are published in this issue of the journal Nature. All three experiments are at the basic science stage, involving investigation of cell lines in the laboratory. As such, the findings are a long way from application in human medicine.

"This finding is exciting because we all want to know the molecular events that lead to cancers," says Zhenkun Lou, Ph.D., a researcher with the Mayo Clinic Cancer Center and a member of the team that found the MDC1 gene. "If we can figure out where genes get messed up, we can screen people for that gene. And if we have gene therapy, we may be able to actually repair the gene and hopefully stop the cancer or prevent a person from getting cancer."

The three research groups decided to announce their findings together when they met at a scientific meeting and realized they were on the same discovery path.

How it works Most researchers think cancers are basically caused by "genomic instability," which means abnormalities within genes. One cause of instability is DNA damage — from ultraviolet radiation, for example — that doesn't get repaired. Cells are constantly damaged, and normally the body is capable of repairing this damage through DNA damage response pathways. Part of these pathways is a checkpoint that gets activated to stop an unhealthy cell from reproducing.

"It's like a warning light in a car," says Dr. Lou. "The checkpoint in a car is the dashboard light that tells you to stop and repair the problem, otherwise the car may breakdown or crash. The checkpoint in the cell is like the warning light for the cell to stop growing and replicating, to give the cell time to repair the damage."

If cells can't be repaired and keep growing abnormally, cancers can occur.

Why MDC1 is important: The development of cancer is a hierarchical series of missteps that occurs within our bodies. Researchers refer to the very earliest missteps, or mutations, as "upstream" of the actual disease. In this illustration, a given cancer is the downstream endpoint. The point researchers are after is the "headwaters" of cancer: the actual first step and ultimate beginning of the chain of events. They want to know what goes wrong first and how the series of events progresses to cancer. MDC1 is important because it appears to be farther upstream than most previously described genes. An error here profoundly affects what happens downstream.

Here's how the cancer-development hierarchy appears to work: A mutation — a break, insertion or rearrangement of genetic material — in an upstream gene is necessary for a downstream gene mutation to proceed.

Mayo Clinic Cancer Center researchers believe MDC1 and another checkpoint protein, ChK2, are upstream of P53, a gene that is mutated in more than 50 percent of cancers of all types. Errors in MDC1 can affect whether P53 gets activated. In a separate report in press in Journal of Biological Chemistry, they reported MDC1 is upstream of previously described vulnerable genes such as BRCA1, which is known to be mutated in more than 50 percent of familial breast cancers.

The next step in the research is to determine if the findings hold up in animals. Dr. Lou says Mayo Clinic Cancer Center researchers are developing an animal model in which the MDC1 gene is disrupted to see if the animal does, in fact, develop cancer.
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CONTACT:
Mary Lawson
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e-mail: newsbureau@mayo.edu

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