Researchers at the Alpert Medical School made an important discovery that may lead to changes in the way brain tumors are diagnosed and treated. Their findings, published in the Journal of the National Cancer Institute last month, have generated a slew of questions not only on brain tumors but also about cancer in general.
"This is a very big deal in brain tumors," said Professor of Community Health Karl Kelsey, one of the paper's senior authors.
Brown researchers collaborated with researchers from the University of California at San Francisco and several other universities. Kelsey and UCSF Professor John Wiencke — who have been friends since high school — have teamed up repeatedly over the last 25 years on various scientific projects.
The study originated from the hypothesis that a relationship exists between mutations in tumors and the methylation patterns found in their genomes, Kelsey said. Previous research had identified this connection in other types of cancer, said Brock Christensen, a Brown postdoctoral research associate in pathology and laboratory medicine and the first author on the paper. He said he — along with Kelsey and Ashley Smith GS — set out to discover if this relationship also existed in brain tumors. There was an even greater basis for the relationship than expected, Kelsey said.
Christensen said the mutation in question exists in the IDH gene, which codes for an enzyme involved in glucose sensing, an aspect of metabolic processing. The researchers found that tumors with this mutation also have an associated DNA methylation pattern.
DNA methylation — when a methyl group is covalently bonded to a cytosine base followed by a guanine base — is an epigenetic alternation to DNA, which changes gene expression. All the cells in the human body contain the same genetic material, but each cell also contains a methylation pattern. Methylated DNA is a signal of gene silencing, Kelsey said. In the case of the brain tumors, the methylated regions marked genes involved in metabolic processes, which might explain the abnormal behavior of tumor cells.
Smith was in charge of the mutation aspect of the analysis, and Christensen handled the epigenetic side. A technique called the Illumina GoldenGate methylation array was used to measure the amount of methylation in the tumors. The analysis revealed a close link between the IDH mutation and enhanced occurrence of methylation, Kelsey said.
The reason for this link is unknown, though research is already underway to fill in the missing gaps. But the Brown research team is going to focus on more general tumor-related questions. "We study tumors and we study people, and the answers to the questions that we have posed are best tackled by biochemists and the pharmaceutical industry," Kelsey said.
The study also found that patients with brain tumors carrying the IDH mutation survive longer than those without the mutation, but Kelsey said no one knows why. Despite this finding, pharmaceutical companies are trying to develop a drug to inhibit methylation, which is counterintuitive, Christensen said. The reasoning is that by preventing the methylation — and therefore reversing the silencing of genes — the cell will return to its normal state, Kelsey said. "But first you have to realize that everybody dies of this disease," he added. The difference in survival is a matter of months or a few years, he said.
But Christensen and Kelsey said they are hopeful that their research will contribute to changes in the way cancer is treated, moving away from the nonspecific and toxic removal of tissue to more personalized medicine. The immediate impact of the research is that people may now measure for IDH mutation clinically, Christensen said. "Just to tell people. Just to be able to say you are maybe going to do a little bit better," he said.
"While there are gaps in the basic biology, we now have targets that clearly affect the character of the tumor," Kelsey said. "That's knowledge that's really important in terms of trying to figure out how to affect treatment."
