Brain Cancers Reveal Novel Genetic Disruption in DNA

A glioma is the most common type of malignant brain tumor in adults. Researchers found that a merging of genetic neighborhoods in brain cells caused them to become cancerous

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Brain cancer has been extensively studied for years, yet doctors have made little progress in treating this disease. Recently, a research team led by Dr. Bradley E. Bernstein from the Broad Institute has suggested that a housekeeping gene encoding a humdrum metabolic enzyme is responsible for a series of downstream cascades that eventually lead to cells turning cancerous. This discovery suggests that long-existing small molecule chemotherapeutics might come back into use and might be powerful enough as a cure. “What this tells me is that I know a lot less than I did before,” said Dr. Jeremy Rich, a brain cancer expert at the Cleveland Clinic.

Gliomas are the most common type of malignant brain tumor. The most aggressive gliomas – known as glioblastoma normally strikes elderly people with an average survival time of only 18 months. The low-grade gliomas tend to hit younger adults with a longer median survival time of up to 10 years. The standard treatment for gliomas are chemotherapy and radiation. However, if the tumor returns, it normally develops into glioblastoma that standard treatment no longer works. “We are desperate in this disease,” Dr. Peter Dirks – a brain cancer expert from Toronto said.

Yet researchers did notice one puzzling feature that 80% of low-to-moderate gliomas patients carry a mutation in a humdrum housekeeping gene, which encodes a metabolic enzyme isocitrate dehydrogenase (IDH). “It was really surprising,” Dr. Bernstein said. “Why would a metabolism gene cause cancer?” And why is it mutated so often?

Starting from this intriguing clue, researchers found that once IDH is mutated, the DNA becomes decorated with chemical tags known as methyl groups. It is already known that DNA is packed tightly on chromosome as autonomous loops, and Dr. Bernstein’s team found that those decorated methyl group tags will remove the walls of the autonomous DNA loops – a protein called CTCF. The removal of the CTCF wall further leads to the merger of neighboring DNA loops. Subsequently, the merged loops will wake up a growth gene called PDGFRA that makes cells continuously grow, and consequently triggers cancerous growth.

To test the proposal, Dr. Bernstein’s team grew glioma cells ex vivo and treated them with a first-generation chemotherapeutic that can dissolve methyl groups. The autonomous DNA loops were reformed and the growth gene PDGFRA was turned off as a result of the recovery of DNA 3D structure.

Their groundbreaking findings suggest that chemotherapy drugs that can dissolve methyl groups can treat people with brain tumors discovered early on. Clinical trials on brain tumors will be starting very soon. On top of that, this method is potentially applicable to other cancers that carry excessive methyl groups on their DNA, including liver cancers, sarcomas, colon cancers, bladder cancers and leukemia.

“I am biased, obviously,” Dr. Bernstein said. But, he added, “I am really optimistic about the potential of this information.”

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