A genetic mutation that prevents cell death may hold the key to treating deadly brain tumors.
The mutation affects the TERT promoter gene, which affects cell division, and is correlated strongly to certain types of brain tumor but not others, a team of Duke researchers found. The discovery, published online in the Proceedings of the National Academy of Sciences Monday, offers a new metric for diagnosing the most common brain tumors and opens up new lines of research to understand the mechanism by which the mutation leads to cancerous tumor growth.
“The discovery of TERT mutation provides the strongest genetic evidence explaining how cancer cells can live for such a long period of time,” co-author and pathology professor Dr. Hai Yan wrote in an email Tuesday. “It brings clarity in tumor classification and diagnosis to guide future personalized treatment.”
The scientists found TERT mutations in 83 percent of adult glioblastomas studied, making it more prevalent than any other kind of mutation in that tumor. This prevalence indicates the TERT mutation may play a key role in glioblastoma development, making it a promising target for drug development. Drugs have been sparse for brain tumors—when the FDA approved the drug Temodar in 2009, it was the first new chemotherapy for brain tumors in 20 years.
The TERT promoter regulates the production of telomerase, the enzyme that controls growth of telomeres, the genetic caps on the end of chromosomes. As cells divide, telomeres progressively get shorter, and in the absence of telomerase, these cells would be signaled for cell death. In the cancers examined in the study, however, the TERT mutation produces higher rates of telomerase, which allows the uninhibited growth of cancer cells.
“These cells would normally be signaled for cell death—as you age in cells telomeres get shorter,” said co-lead author Patrick Killela, a fourth-year Ph.D. student in pathology. “Normally the body would signal these cells to die. However, a way cells avoid this fate is to upregulate telomerase.... As long as it has the proper signals, cancer cells will divide ad infinitum.”
The research came out of Yan’s lab at the Preston Robert Tisch Brain Tumor Center, as a follow-up to a study published in January. The lab combines state of the art equipment for gene sequencing and a highly annotated collection of brain samples, which made it possible for the researchers to analyze 1,230 tumors including 60 varieties in approximately two months. Researchers at other schools contributed as well, including several from Johns Hopkins University.
The data on the TERT mutation provides a new tool for differentiating which type of brain tumor a patient has. The currently available pathology tests are not always able to distinguish similar brain tumors, said Zachary Reitman, a postdoctoral researcher in the Yan Lab.
“There is a huge problem when a patient comes into the clinic and perhaps has had a seizure and an MRI showing a tumor—sometimes we have trouble telling them which type of tumor it is,” he said. “We can’t tell the patient for sure how aggressive we expect it to be, whether we expect them to have less than one-year survival or 10-year survival.”
The new findings, combined with previous Yan Lab research on mutations of the IDH1 and 2 genes in brain tumors, suggest a way of differentiating the three most common brain tumors, Killela said. Glioblastomas, the most deadly brain tumors, are strongly correlated with TERT mutation but not with IDH mutations. Astrocytomas tend to have IDH gene mutations but not TERT mutations. Oligodendrogliomas are correlated with both TERT and IDH mutations.
Successfully differentiating these tumors early on will give patients and doctors more time to properly treat the tumor, and generate more accurate prognoses.
Because the study establishes the TERT gene mutation as a consistent biomarker for certain cancerous tumors, future research will focus on how exactly the mutation contributes to cancer growth, Reitman said. The lab is already at work studying cell lines—human tumor cells grown in a petri dish—to explore the biological mechanism by which the mutation causes tumors to grow.
“First we need a better understanding of just what this is doing,” Reitman said. “Then we could design a drug to counteract the effects of the mutation.”
There is good precedent for the success of drugs that target a mutation associated with a tumor and thereby stop the tumor, Reitman added. This was the approach taken in developing the drug Gleevec to effectively combat chronic myelogenous leukemia. Research into the TERT mutation is still in early stages, but the researchers aim to eventually apply the knowledge to a similar drug.
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