Variant In Gene Associated With Telomeres Predicts Longer Survival of Deadly Brain Tumor
M. D. Anderson News Release 04/18/05
An exceptionally large study of patients with glioblastoma multiforme has found an association between a genetic variation and a doubling of survival rate ¯ the strongest link ever established between genetic variation and outcome in this deadliest form of brain cancer, according to researchers at The University of Texas M. D. Anderson Cancer Center.
The study, presented at the annual meeting of the American Association of Cancer Research, found the differences in a common variant in a number of repeats (short or long) of the hTERT gene, which produces human telomerase.
This study of 301 patients, which the researchers believe is the largest to date of patients with glioblastoma multiforme, found that the 36 patients (about 11 percent) who had the “SS” variant genotype of hTERT survived an average of 25 months, compared to about 14 months for those who had either the “SL” or “LL” genotypes.
The findings are exciting, says the lead investigator, Melissa Bondy, Ph.D., a professor in the Department of Epidemiology, because they suggest new treatment directions for patients with a cancer that is both the most common glioma and the one offering the poorest hope of survival.
“It is a real advance because we have never seen any genotype that can stratify glioblastoma multiforme patients into different treatment outcome groups like this,” says Bondy. “Now we need to verify the finding, study the mechanism, and see if there is a way that these results can be used either as a biomarker or to individualize treatment.”
For example, if the SS variant genotype of hTERT is confirmed to have better response to chemotherapy and radiation treatment, then it is possible that these therapies will extend survival for patients with glioblastoma multiforme, she says.
Telomeres, the structures that cap the end of cellular chromosomes, have been linked to both the aging process and cancer development. Telomerase is an enzyme that helps regulate the length of telomeres, and in normal cells, it is not generally active past fetal development. Thus, telomeres shorten each time a cell divides, until they cannot protect chromosomes and the cell dies. But in cancer, it is believed that telomerase is activated and intervenes to keep telomeres from shortening, allowing for unlimited cell division.
The research group looked at genetic variation of hTERT because abnormal expression of the gene contributes to unregulated cell growth, and expression of the gene has been evaluated as one of the most common tumor markers in most primary tumors, says the study’s first author, Luo Wang, M.D., Ph.D., a research scientist in the Department of Epidemiology.
The mechanism why the SS variant genotype of hTERT showed better survival remains unknown. But some forms of hTERT may be less destructive than others because they may be expressed at a lower level, Wang says. For instance, the SS variant genotype is more likely than the SL or LL variant genotype to produce an antisense-like molecule that suppresses the expression of human telomerase, he says, and this modulation may enhance the effect of the chemotherapy and radiation treatment on the patients with the SS variant genotype.
Bondy says the association between the SS variant genotype and improved outcome held, even when differences in age, sex and the extent of surgery, chemotherapy and radiation were taken into account. “We have looked at a lot of different genes associated with cancer, such as DNA repair genes and p53, but this is the first time we have found a genotype that has such a large effect on clinical outcome.”