Genes that drive brain cancer revealed

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About 15% of patients with glioblastoma could receive personalized treatment with drugs currently used in other cancers, based on new research that has identified 18 genes responsible for driving glioblastoma multiforme.

"Cancers rely on driver genes to remain cancers, and driver genes are the best targets for therapy," said co-author Antonio Iavarone, MD, professor of pathology and neurology at Columbia University Medical Center in New York, New York. In any single tumor, hundreds of genes may be mutated, but distinguishing the mutations that drive cancer from mutations that have no effect has been a long-standing problem for researchers.

"Once you know the driver in a particular tumor and you hit it, the cancer collapses. We think our study has identified the vast majority of drivers in glioblastoma, and therefore a list of the most important targets for glioblastoma drug development and the basis for personalized treatment of brain cancer."

The Columbia team used a combination of high-throughput DNA sequencing and a new method of statistical analysis to generate a short list of driver candidates. The massive study of nearly 140 brain tumors sequenced the DNA and RNA of every gene in the tumors to identify all the mutations in each tumor. A statistical algorithm designed by co-author Raul Rabadan, PhD, assistant professor of biomedical informatics and systems biology, was then used to identify the mutations most likely to be driver mutations. The algorithm differs from other techniques to distinguish drivers from other mutations in that it considers not only how often the gene is mutated in different tumors but also the manner in which it is mutated.

"If one copy of the gene in a tumor is mutated at a single point and the second copy is mutated in a different way, there's a higher probability that the gene is a driver," Iavarone said. The analysis identified 15 driver genes that had been previously identified in other studies—confirming the accuracy of the technique—and 18 new driver genes that had never been implicated in glioblastoma.

Significantly, some of the most important candidates among the 18 new genes, such as LZTR1 and delta catenin, were confirmed to be driver genes in laboratory studies involving cancer stem cells taken from human tumors and examined in culture, as well as after they had been implanted into mice.

Because patients' tumors are “powered” by different driver genes, the researchers say that a complicated analysis will be needed for personalized glioblastoma treatment to become a reality. First, all the genes in a patient's tumor must be sequenced and analyzed to identify its driver gene. Then the candidate driver needs to be confirmed.

"In some tumors it's obvious what the driver is; but in others, it's harder to figure out," said Iavarone. For 15% of patients whose tumors are driven by certain gene fusions, FDA-approved drugs that target those drivers are currently available.

This study was published in Nature Genetics (2013; doi:10.1038/ng.2734).
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