Tracing cancer back to its origin is like trying to reconstruct a crime. Which genetic mutations are clues to cancer’s origins, and which are red herrings? Many cases of a supratentorial ependymoma, one of the more common brain cancers in children, share a specific gene fusion — but is it causing the tumors? In work published today in Cell Reports, researchers at Fred Hutchinson Cancer Research Center showed that the gene fusion is enough to trigger tumor formation in otherwise normal brain cells.
“The paper proves that this gene fusion, caused by a chromosomal event called chromothripsis, is very likely the first event and the actual cause of the disease in humans,” said senior author Dr. Eric Holland, a neurosurgeon, brain cancer researcher and director of the Human Biology Division at Fred Hutch. “If we knew how to counteract that gene fusion’s effects, we would have a good handle on treating that subset of ependymoma.”
Ependymomas make up about 10 percent of childhood brain tumors and 4 percent of adult brain tumors. Currently, they are all treated the same way: with surgery and radiation. But over the past decade or so, closer examinations of the genetic alterations in ependymomas from different brain regions showed that they’re are not all the same.
“It turns out that tumors that show up in different areas of the brain are different diseases from a molecular standpoint,” said Holland.
Supratentorial, or ST-ependymomas, the type Holland’s team focused on in the study, are located above, or supra, the tentorium, the membrane separating the cerebellum (a small region located just above the neck) from the cortex, which makes up most of the brain.
While other kinds of cancer accumulate many mutations over time, ST-ependymomas undergo chromothripsis, a catastrophic rearrangement in one section of their DNA.
“It looks like a region of the DNA blew up,” Holland explained. “There are pieces of it shifted around, shuffled and pasted back together.”
About three-quarters of the time, this genetic explosion fuses to specific genes, RelA and C11orf95, together. Patients whose tumors carry this fusion have a five-year, progression-free survival rate of less than 30 percent, compared to the 67 percent five-year, progression-free survival rate seen in patients with a different fusion. Patients need better treatment options, and a tumor’s DNA is a good place to start looking for potential therapeutic targets.
But it wasn’t clear whether this fusion actually caused tumors. In previous work by one of the study’s co-authors, cells genetically manipulated to carry the fusion caused tumors after being injected into mice. But these data didn’t definitively answer the question of whether this fusion triggered cancers in otherwise normal neural cells.
To see whether the RelA–C11orf95 fusion was enough to trigger ST-ependymomas, first author Tatsuya Ozawa, a staff scientist in the Holland Lab, used an approach Holland had previously developed that allows genes to be inserted into specific neural cell types in mice.
Ozawa and the team compared tumor formation in mice given the RelA-C11orf95 fusion against mice given just RelA. As many as 92 percent of mice who received the fusion developed tumors within two months. Mice that only received RelA didn’t develop any tumors. Strikingly, the fusion caused tumors in the absence of other genetic alterations, and even alterations that strongly promote cancer in other brain tumor models didn’t enhance ependymoma formation. This showed that the RelA–C11orf95 fusion was enough to cause tumor formation on its own.
When the researchers characterized the tumors from the mice given the fusion, they found that they shared many physical characteristics with ependymomas in humans, suggesting that their model could be used to learn more about the biology of the disease. Additionally, the suite of genes turned on in the mouse tumors were similar to those turned on in human ST-ependymomas. Some of these genes modulate how cells stick to each other, suggesting that the RelA–C11orf95 fusion could be turning on genes that help tumor cells invade their surroundings.
And finally, the scientists gained some insight into the cells that give rise to ST-ependymomas. They appear to be neural stem cells that line the ventricles, which are the spaces in the brain filled with cerebrospinal fluid.
The new model is the most genetically relevant model of ST-ependymoma, Holland said. Understanding that the RelA–C11orf95 fusion doesn’t require any other genetic abnormalities to cause cancer is important, he said, because “If you know what the causal event is, it’s likely to be a pretty good therapeutic target —if you could figure out how to target it.”
Chronic myeloid leukemia is another tumor type that is driven by a single gene fusion. This gene fusion can be directly inhibited with the drug Gleevec, which stops CML in its tracks. Unfortunately, the RelA–C11orf95 fusion isn’t such an easy target. The researchers found that just blocking RelA — the only gene in the fusion with a known function — isn’t enough to prevent ependymomas. But if a drug could be developed that specifically targeted this gene fusion, it could be tested in this model, co-author Dr. Frank Szulzewsky, a postdoctoral research fellow in the Holland Lab, wrote in an email.
In addition to working to discover how, exactly, the RelA–C11orf95 fusion causes cancer, Holland is exploring potential therapeutic strategies beyond small molecules that could block the fusion. In particular, the potential to turn the immune system against tumors that express a unique target — the gene fusion — not found in healthy cells.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Research Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.