‘Whole new way in’ to brain tumors

BROWN U. (US) — A specific genetic mutation appears to be at the center of a metabolic meltdown associated with lethal brain tumors known as gliomas.

While the discovery leaves many questions about brain tumors unanswered—among them is what causes the mutation, what causes the mutation to affect other genes in the cell, and most, importantly, what is the best way take therapeutic advantage of these new observations—the findings suggest it may be possible for drug makers to target the abnormal process as a way to control tumor growth.

“Gliomas are such a deadly disease, and so little is known about them, that people are pretty excited about this because it is a whole new way in,” says Karl Kelsey, professor of pathology and laboratory medicine and community health at Brown University. “We have a new clue about what to study.”

Details are reported in the Journal of the National Cancer Institute.

Scientists have known for a couple of years that a mutation in a gene called IDH is associated with glioma. They have also observed that people with gliomas carrying the mutation survive longer than those afflicted with tumors lacking the mutation.

What the new study shows is that the mutation is associated with a consistent pattern of an alteration known as “methylation” of the DNA which is associated with changes in gene expression. The pattern of methylation in tumors with the IDH mutation often occurred in metabolic genes, regardless of the tumor’s specific type.

Margaret Wrensch, professor of neurological surgery, epidemiology and biostatistics at the University of California, San Francisco, says what the team found surprising is that DNA from almost all tumors with IDH mutations had the same distinctive methylation pattern. The degree of methylation throughout the genome was unusually high, and the same specific DNA was methylated.

“This one mutation is common to a whole subset of brain tumors,” she adds. “It’s quite unique. It seems to dominate other mutations in the tumor and the epigenetic changes are very uniform.”

The researchers hope now that if a drug could inhibit this methylation process in any number of these affected genes, not necessarily just IDH, that might correct the errant metabolism of the tumors and control their growth.

“We know now that there are all these genes related to metabolism that have altered methylation,” says Brock Christensen, a Brown postdoctoral scholar in pathology and laboratory medicine and a lead author of the paper, which also involved researchers from the University of Minnesota and Dartmouth Medical School. “In this suite of genes there might be a much easier target to try to design a therapy for.”

The heart of the study was a tumor-by-tumor analysis of the methlylation in scores of samples. The analysis revealed an unusually ironclad correlation between the IDH mutation and methylation in metabolic genes in gliomas of many different names and classifications.

“The strength of the correlation was absolutely stunning,” Christensen says. “It’s not the kind of thing you see very often in cancer epidemiology, to have almost all of these mutant tumors having the same methylation profile.”

The IDH gene has a role in glucose sensing, so the association of the mutation with altered metabolism genes (occurring through enhanced DNA methylation) is reasonable, Christensen said. The researchers are now looking into the role that mutation in IDH plays in perhaps altering other metabolism genes in the cells.

The research was funded by the National Institutes of Health.

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