Geneticists link 'junk' DNA to Ewing's sarcoma

If there is such a thing as a diamond in the rough in cancer research, geneticists at Huntsman Cancer Institute could well have discovered one lying in the junk regions of DNA.

For the first time, the small DNA sequences that tend to have no known function have been linked as a cause of cancer, in particular Ewing's sarcoma, an aggressive form of bone cancer that strikes children and young adults.

Although researchers have focused on these so-called "microsatellites" as markers for other genetic studies, this was the first time that they were found to have an active role in the development of cancer, institute investigators report in today's edition of the on-line journal Oncogene.

The study also sheds new light on one of the troubling aspects of the disease — why some patients with Ewing's sarcoma respond to chemotherapy treatment better than other patients, even though they have the same form of cancer.

Researchers found that the poorer a patient did on chemotherapy, the higher their levels of a protein known as GSTM4, which seems to have an ability to suppress the effectiveness of the chemicals on the cancer. Among patients who fared better, the protein levels were low.

The protein is apparently attempting to detoxify the chemicals used in the therapy and as a result are less effective on the tumor than in patients who don't have high levels, said Dr. Stephen Lessnick, an institute investigator and co-author of the study.

As with all cancer research, each finding seems to unlock another set of complications: GSTM4 doesn't seem to suppress the benefits of all chemotherapy drugs, just certain ones. A GSTM4-based screening of patients would help take the guesswork out of identifying the best therapy for each patient as well as lead to drugs that are able to suppress the protein levels in some patients, Lessnick said.

"We then asked where are a particular subset of microsatellites in the human genome, and what genes are next to these. One of these was GSTM4, and so we were able to show that EWS/FLI causes GSTM4 to get turned on through its microsatellite, and that gave us the impetus to study GSTM4 in more detail," Lessnick told the Deseret News.

Within Ewing's sarcoma tumors, an abnormal protein-EWS-FLI is the "master regulator" that causes this type of mostly bone cancer, which is diagnosed in about 300 children and an estimated 200 to 300 young adults in the United States each year. Between six and 10 cases are diagnosed annually at the Huntsman Cancer Institute and Primary Children's Medical Center, Lessnick said.