In Brain Cancer, Unique Genetic and "Epigenetic" Profile Means Better Odds

By Jeffrey Norris

John WienckeJohn Wiencke
Brain cancers are deadly more often than not, but UCSF researchers have determined that a particular genetic signature is associated with longer survival. The discovery, reported online December 15 in the Journal of the National Cancer Institute, may lead to a better understanding of how certain cancers can arise and lead to better therapies for some of the deadliest brain cancers, for which there is no curative treatment. Brain cancers cause 13,000 deaths in the US each year. A majority are advanced, grade-IV glioblastomas at the time of diagnosis. Even with surgery and radiation or chemotherapy, less than one in 20 individuals with a glioblastoma diagnosis remains alive after five years. Half die within one year.
Margaret WrenschMargaret Wrensch
Yet across all grades of brain tumors, including glioblastomas, the presence of an abnormally altered version of a gene called IDH is associated with improved survival, the UCSF researchers report. The research was led by John Wiencke, PhD, and Margaret Wrensch, PhD, both professors in the Department of Neurological Surgery at UCSF and members of the UCSF Helen Diller Family Comprehensive Cancer Center, along with Karl Kelsey, MD, of Brown University. Their research group analyzed clinical data and brain tumor samples from the UCSF Brain Tumor Research Center’s Tissue Bank. The study included samples from 131 patients who had been treated by UCSF Department of Neurological Surgery physicians.

Brain Cancers with IDH Mutations are Distinctive

A patient with the IDH tumor mutation was four times more likely to survive longer than a patient with a similar tumor that lacked the mutation. The survival benefit was independent of the influence of other patient and tumor characteristics that are commonly charted in clinical pathology labs, such as age and tumor subtype. Within the last few years the IDH mutation has been found to be associated with brain tumors and with a type of leukemia. Most strikingly, the UCSF team has found that the mutation is associated with a distinctive “epigenetic” fingerprint within tumors. It’s still early days when it comes to understanding what these fingerprints mean in cancers and how to use the information to battle tumors. Changes in the epigenetic characteristics of DNA do not change the tumor’s genetic code – no substitutions are made in the alphabet building blocks that spell out a DNA sequence. But epigenetic changes do affect whether or not genes are active – whether a gene tells a cell to make its encoded protein, for instance. Methylation of DNA – the addition of a carbon-containing molecule – is one such epigenetic event that can affect whether the DNA is active. In this way methylation patterns shape cell form, growth, function and identity. Changing methylation patterns guide the complex development of growing organisms. In humans the result is the generation of hundreds of different tissue types that work together to form the whole. It is no surprise that abnormal tumor cells possess abnormal methylation patterns. Any collection of brain tumors typically displays a wide range of abnormal methylation patterns. However, what was surprising to the UCSF researchers in their latest study 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,” Wrensch says. “It’s quite unique. It seems to dominate other mutations in the tumor and the epigenetic changes are very uniform.”

Metabolism Advantage for Tumors Suspected

The IDH mutation was present in less than 10 percent of brain cancers diagnosed as grade IV glioblastomas, but was detected in 80 percent of lower grade brain tumors. Although the cancers generally proved fatal in each type of brain cancer, the presence of the mutation was associated with longer survival compared to tumors of the same grade that lacked the mutation. Because brain tumors with IDH mutations may arise by a common pathway, it may be possible to identify key biochemical events and molecules along this path to tumor formation. These molecules could be targeted for new drug development efforts aimed at tumors with this distinctive fingerprint, the UCSF researchers say. The protein made according to the instructions encoded by the IDH gene is involved in sugar metabolism, a source of energy for cells. Tumors are believed to require more energy than normal tissue to fuel uncontrolled growth. The methylation pattern of DNA associated with the IDH mutation is associated with a ramping up of metabolic pathways. Wiencke speculates that the metabolic role of the IDH mutation may play a role in tumor formation. The idea that glucose metabolism fuels cancer growth is a very old one, Wiencke says, dating back to the 1920s. It fell out of favor, but may be making a comeback. “How tumor cells get their energy is still mysterious,” he says. “The fact that the same epigenetic pattern is in different types of brain cancers suggests that there is a common factor that drives the pattern -- IDH mutation. Altered metabolism may be playing a role in these cancers.”
IDH Mutation Defines Methylation Class and Survival in Human Glioma
Brock C. Christensen, Ashley A. Smith, Shichun Zheng, Devin C. Koestler, E. Andres Houseman, Carmen J. Marsit, Joseph L. Wiemels, Heather H. Nelson, Margaret R. Karagas, Margaret R. Wrensch, Karl T. Kelsey, John K. Wiencke
JNCI, August, 15, 2010

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Brain Cancer Linked to Inherited Genetic Risk
UCSF Science Café, July 5, 2010 UCSF Helen Diller Family Comprehensive Cancer Center