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New Gene Markings for a Deadly Brain Cancer

19 February 2009 (All day)
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Photograph courtesy of Duke Photopath

Telling tumor. A genetic mutation could help doctors diagnose deadly tumors in the brain.

While survival rates for many cancers have improved over the years, brain cancers often remain stubbornly unresponsive to treatment. Now, researchers are turning to genetics and have hit on a gene mutation that can be used to differentiate between the deadliest brain cancers. The find could help doctors more accurately diagnose these devastating tumors.

The most common brain tumor, glioblastoma, is also the deadliest. These tumors occur in two forms: primary, in which patients suddenly develop large and highly malignant tumors, and secondary glioblastomas, which begin as smaller, less aggressive tumors in the brain. Last fall, scientists reported an intriguing difference in the genetics of these two types of tumors. A particular mutation showed up in secondary tumors (Science, 4 September 2008, p. 1807). Patients with the mutation also seemed to have better prognoses than did those without it.

The researchers, led by D. Williams Parsons of Johns Hopkins University in Baltimore, Maryland, and Hai Yan of Duke University in Durham, North Carolina, were intrigued because the gene had not been previously implicated in cancer. The gene, called isocitrate dehydrogenase-1 (IDH1), codes for an important enzyme in cell metabolism. The researchers decided to sequence more brain tumors to verify what kinds of mutations occur in the IDH1 gene and how they impact cancer cells.

They sampled DNA from 445 brain tumors that had been removed from patients at various stages in development. Of these, 170 carried a mutated form of either IDH1 or its cousin gene, IDH2. Most of the mutated tumors were either secondary glioblastomas or other, less aggressive tumors, confirming last year's work, the researchers report online this week in The New England Journal of Medicine. Importantly, every tumor with a mutant gene had a single letter change in roughly the same location on the gene, which may make it easier to use as a biomarker because it's relatively easy to spot.

Then the researchers found that in brain cancer cells in the lab, enzymes that typically produce energy were virtually inactive in mutated cells compared with normal IDH cells--suggesting that these cells aren't metabolizing energy as efficiently and have less to grow on. Despite the results of the Science paper and this one, Yan says the mutation may not actually be protecting patients. It could just be signaling tumors to grow, albeit not as aggressively as in primary glioblastomas--but its function is far from clear right now. This is important because the two kinds of tumors can look very similar under the microscope, notes pathologist Roger McLendon of Duke, who also participated in the research. Testing for the IDH mutation could allow doctors to more accurately diagnose the disease, Yan says.

Whether the findings will lead to new treatments is unclear at this point, says cancer biologist William Hahn of the Dana-Farber Cancer Institute in Boston. But just using the mutation as a diagnostic tool would be a boon for brain cancer treatment, he says. "We're all hoping we'll have molecular markers to distinguish which tumors will do well or poorly."

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