Researchers discover genomic variant that increases brain tumor risk

Volume 1, Issue 3, 2012
Robert B. Jenkins, M.D., Ph.D., a Mayo Clinic Cancer Center pathologist

Robert B. Jenkins, M.D., Ph.D.

People who carry a guanine (G) instead of an adenine (A) at a specific spot in their genetic code have roughly a sixfold higher risk of developing certain types of brain tumors, a Mayo Clinic and University of California, San Francisco, study has found. The findings, published online in the journal Nature Genetics, could help researchers identify people at risk of developing certain subtypes of gliomas, which account for about 20 percent of new brain cancers diagnosed annually in the United States. The findings also could lead to better surveillance, diagnosis and treatment.

Researchers still have to confirm whether the spot is the source of tumors, but if it's not, "it is pretty close," said senior author Robert B. Jenkins, M.D., Ph.D., a pathologist at the Mayo Clinic Cancer Center and the Ting Tsung and Wei Fong Chao Professor of Individualized Medicine Research at Mayo Clinic. "Based on our findings, we are already starting to think about clinical tests that can tell patients with abnormal brain scans what kind of tumor they have, just by testing their blood."

A few years ago, researchers began hunting for regions of the genome that might be associated with the development of gliomas. These researchers observed a portion of chromosome 8 that contained single nucleotide polymorphisms, or SNPs, associated with brain tumors. Since then, Dr. Jenkins and Margaret Wrensch, Ph.D., professor of neurological surgery at the University of California, San Francisco, have been using a combination of sophisticated genomic techniques to search for the specific SNP causing brain tumors to form.

They honed in on seven candidates. One — the SNP called rs55705857 — confers a relative risk approaching that seen with BRCA1, a breast cancer gene. This region was only found through the most laborious method used by the researchers — next-generation sequencing — suggesting that experimental and mathematical shortcuts may miss such rare, highly potent gene variants, Dr. Jenkins said.

Drs. Jenkins and Wrensch found that having the G version of this SNP — rather than the more common A version — was strongly associated with slower growing gliomas.

"Being able to tell people that the mass in their brain is this type of tumor is actually good news, because it has a much better prognosis than other brain tumors," Dr. Jenkins said. "So what is it that predisposes people to develop less aggressive, but still lethal, gliomas? That makes understanding the function of this variant even more important."

As part of their work, the researchers compared the sequence of the gene variant throughout mammalian evolution and found that it has been conserved as far back as the ancient platypus — as human's most distant genetic relative, the platypus has provided a wealth of information on the nature of the human genome. Computer modeling indicated that the region may be a microRNA, a special kind of nucleic acid that controls the activity of genetic messages within cells. The modeling placed the SNP within the functional part of the microRNA, suggesting that a change in genetic code from an A to a G could have significant consequences. The research team is investigating whether the microRNA actually exists, and what its functional implications might be.

"The altered microRNA might target tumor suppressor genes, it might activate a cancer gene, it might be involved in regulating the stability of the genome, or there might be something else going on altogether," Dr. Jenkins said. "One of the big challenges of the current genomic era is to assign functions to all these new gene variants."

Finding the "G" that Increases Risk of Certain Brain Tumors

Watch a video of Dr. Jenkins discussing this study.

23,000 people are diagnosed with malignant brain cancer in the United States every year. Most of those cancers are glioblastoma, which is a very aggressive brain tumor. The association we have found is with the subclass of brain cancer which occurs in about 20% of people that have malignant brain tumors. So one of the things we're most excited about is, we have found a particular germ line alteration that predisposes the development of this 20% of brain cancer.

Mayo Clinic UCSF Study 1

View animation illustrating this genomic variant.