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NeuroNow - Giving brain cancer the one-two punch

NeuroNow Fall 2011

Giving brain cancer the one-two punch

Date: November 21, 2011

Bettegowda, Kinzler, Papadopoulos
Along with colleagues across Johns Hopkins, Chetan Bettegowda, Ken Kinzler and Nick Papadopoulos recently published groundbreaking research on a common form of brain cancer.

Many scientists believe that cancers develop through a process called the “two-hit” theory. The first hit happens when a pivotal gene on one of the body’s 23 chromosomes is damaged or deleted. However, since each cell has two copies of genes, one on each chromosome, all isn’t lost—the second copy of the affected gene can usually act in its stead. However, if that other copy also fails, this second blow can lead cells to catastrophically multiply and spread throughout the body, the hallmarks of cancer.

In the second-most common form of brain cancer, a type known as oligodendroglioma, researchers had long ago discovered what they suspected was the first hit. In about 70 percent of patients with this disease, stretches of chromosomes 1 and 19 are fused together, resulting in the loss of many genes on each chromosome. However, the second hit remained a mystery. What additional strike pushes these brain cells over the edge, into cancer?

Recently, Johns Hopkins scientists including neurosurgery resident Chetan Bettegowda, professor Kenneth Kinzler and professor Nickolas Papadopoulos published a paper in the prestigious journal Science that seems to hold the answer. In the process of completing a comprehensive map of genetic mutations that occur in oligodendroglioma, compiled through painstaking examination of samples from patients’ tumors, the researchers discovered mutations in genes not previously associated with this cancer. These genes, known as CIC and FUBP1, are on chromosomes 1 and 19, in precisely those areas affected by fusions on the corresponding chromosomes. The researchers found these mutations in about two-thirds of tissue samples.

“Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor,” Papadopoulos says.

With this new clue into the workings of oligodendroglioma, adds Bettegowda, researchers may be able to develop new ways to treat this disease or better wield treatments already at their disposal. For example, he explains, previous studies have shown that patients who have deletions in chromosomes 1 and 19 tend to respond better to chemotherapy and radiation than those whose chromosomes aren’t fused. Bettegowda says the research team’s next step is to test whether patients with CIC and FUBP1 mutations have the same favorable prognosis as those with chromosome deletions.

“We can focus now on when these mutations develop during tumor formation,” he says, “whether they can guide prognosis, and how they might form targets for therapy.”

For oligodendroglioma, which accounts for up to 20 percent of brain cancers and tends to strike people between the ages of 30 and 45, the new advance showcases the power of modern tools researchers are using to more fully understand the underpinnings of cancer, says Kinzler. Oligodendrogliomas are currently treated with surgery, followed by courses of chemotherapy and radiation. However, understanding the genes involved in spurring and propagating this cancer could lead to completely new treatments without the inherent drawbacks of older therapies.

“Thanks to the Human Genome Project and advances in cancer genome sequencing, a single study can now resolve decade-old questions and reveal the genetics of this brain cancer,” Kinzler says. “Knowing the genetic roadmap of a cancer is the key to attacking it.”

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