Enzyme maintaining chromosome ends is linked to bone cancer recurrence, decreased survival

September 23, 2004

Children with the bone tumor osteosarcoma are more likely to experience a recurrence of the cancer after treatment and less likely to survive if the cancer cells are expressing the telomerase gene. This finding, from investigators at St. Jude Children's Research Hospital, appears in the current issue of the Journal of Clinical Oncology (JCO).

Osteosarcoma is the most common primary bone tumor in children. Primary tumors are those originating in a specific place in the body rather than those that have spread from elsewhere. About 30 percent of children with osteosarcoma that has not spread from the bone and 60 percent of those whose tumors have spread do not survive.

"Overall, our results indicate that telomerase gene expression is associated with an unfavorable outcome for children being treated for osteosarcoma," said Jeffrey S. Dome, M.D., associate member in Hematology-Oncology at St. Jude. Dome is senior author of the JCO report. Robert P. Sanders, M.D., a St. Jude postdoctoral fellow, is the paper's first author.

Although study results are preliminary, they might lead to tests that could identify children at high risk for treatment failure or death. That could help physicians determine how to modify therapies to improve chances of success in the future. The findings were based on a retrospective study of samples taken from osteosarcoma tumors of children treated at St. Jude during a 20-year period.

Telomerase is an enzyme that helps cancer cells survive and proliferate. The enzyme builds and maintains caps called telomeres that are located on the ends of chromosomes. These telomeres protect the chromosome ends from damage that otherwise would trigger apoptosis--the cell's self-destruct program.

Most cancers activate telomerase to maintain telomeres in order to protect their chromosomes and ensure the cells survive and multiply.

However, a minority of cancers use a poorly understood mechanism called "alternative lengthening of telomeres" (ALT) to maintain telomeres.

"Osteosarcoma is different from most cancers," Dome said. "Many osteosarcomas don't have telomerase and instead use ALT to maintain telomeres. We found that when these tumors do have telomerase, they are harder to cure."

The St. Jude team used tumor samples from 44 patients to determine the level of telomerase activity that existed at the time the samples were taken. The investigators measured the levels of the mRNA for a part of the telomerase enzyme called TERT, which does the actual work of building maintaining and lengthening telomeres. mRNA is the decoded form of DNA that represents the "active" form of a gene.

The team also tested for the presence of ALT in cancer cells. A total of 14 (32 percent) of the primary tumors expressed TERT mRNA. Of those, eight tumor samples expressed only TERT and six expressed TERT and activated ALT. In addition, a total of 30 (68 percent) did not express TERT mRNA. Of these 30 samples, 29 activated ALT and one had no ALT.

Among children whose tumors contained TERT, only 21 percent experienced progression-free survival (PFS) for the three years studied (that is, their cancers did not return); while among the group without TERT, 64 percent experienced PFS. Also, among those with TERT, about 43 percent survived for at least three years, compared with 70 percent whose tumor cells lacked TERT.

The researchers also studied the rate of PFS among 31 patients whose cancer had not already spread by the time they were found to have with osteosarcoma. Among those whose tumor cells contained TERT, the rate of PFS was 33 percent; while among those whose tumor cells lacked TERT, the rate of PFS was 72 percent.

Finally, among 31 children from whom tumor samples had been taken before chemotherapy began, the PFS over three years was 50 percent in those whose tumor cells contained TERT, compared to 77 percent among those without TERT.
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Other authors of the study are Rachid Drissi, Catherine A. Billups, Najat C. Daw and Marcus B. Valentine.

This work was supported in part by the National Institutes of Health and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay.

St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.

St. Jude Children's Research Hospital

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