Medical Professional Publications

Researchers Report a Rare BRAF Gene Mutation in Brain Cancer

(From the March 2018 issue of Research Now)

Genomic analysis indicates low-grade ganglioglioma can be driven by different mutations, adding to the growing understanding of cancer subtypes

Nationwide Children’s Hospital researchers at the Institute for Genomic Medicine (IGM) have identified a BRAF gene mutation as the likely driver behind a slow-growing brain tumor, called a low-grade ganglioglioma, in an 18-year-old girl. Current studies suggest most children with ganglioglioma don’t have this mutation. The scientists believe their study is the first to identify it in this type of cancer.

The mutation, NM_004333.4:c.1794_1796dupTAC;p.Thr599dup, has been noted as a very rare mutation in a few other cancers and, based on those studies, likely results in an inability to regulate BRAF protein activity and hence interferes with normal cellular signaling.  

Gangliogliomas grow slowly but with the BRAF mutation now confirmed in the IGM clinical laboratory, the treating oncologist could consider a BRAF inhibitor therapy should the tumor progress and begin causing health problems, the researchers say.

“The variant we describe in this patient is extraordinarily rare in gangliogliomas and a few other cancer types,” says Elaine Mardis, PhD, co-executive director of the IGM at Nationwide Children’s and senior author of the study. “I sequenced one other patient with this variant in 2011, who had a low-grade glioma, but due to the nature of the study, it was never reported.”

The researchers report this finding in Molecular Case Studies, an online journal that requires authors to post variants in the public domain as their reports are published, in order to communicate new variants and thereby speed advancements in disease genomics. Dr. Mardis, who is also a professor of pediatrics at The Ohio State University College of Medicine, is editor-in-chief of this journal, but did not handle this paper for the journal.

“One thing we know about cancer is that the same genes are mutated in different cancer types,” Dr. Mardis says. “Reporting a variant in a specific tumor type is important for two reasons. One reason is to provide confirmatory evidence that the specific mutation in that gene has been identified. This type of report will give confidence to other clinical diagnostic assays that also identify this mutation because computationally, this mutation — the insertion of three nucleotides — is hard to predict.  The second reason is to provide additional evidence that the mutation is likely a driver of cancer development.  This is a ‘numbers game’ in that the more frequently a mutation is seen, the more likely it leads to cancer development.  Such evidence also supports that treating a tumor with this type of mutation, using a specific therapy to inhibit the mutated protein, will elicit a response.”

Because next generation sequencing generates so much information, it can be difficult to determine which variants are driving a cancer and which are passengers, she explained. “By virtue of seeing a rare mutation multiple times, you’re building evidence for that type of mutation being a driver.”

The IGM became involved in this case when an MRI indicated that the girl’s brain tumor, first diagnosed in her early teens and kept under observation, had grown.

After a surgical biopsy of the tumor, the IGM used next generation sequencing to compare the genome, exome, and RNA of the cancerous tissue to DNA from the girl’s peripheral blood.

“We performed a lot of molecular testing on this patient and this BRAF mutation is the only clinically relevant finding,” says Katie Miller, PhD, postdoctoral researcher in the IGM and lead author of the study.

The researchers used PCR and Sanger sequencing to amplify and sequence the region of the genome they identified and confirm the mutation in the IGM clinical laboratory. 

“Because of this mutation, the BRAF protein appears to display increased activity — or constant activation,” Dr. Miller says. “Without the mutation, the body would regulate activity of the BRAF protein. With the mutation, the body can’t. When BRAF is constantly activated, this contributes to uncontrolled cell growth and tumor formation.”

The researchers say the primary goal of the sequencing is to provide the girl’s physician with alternatives to standard therapy, should they become necessary.

Publishing the results of sequencing tumor genomes can help researchers and clinicians around the world to understand the fundamental, genetic makeup of cancer subtypes, Dr. Miller says.

The case is one of more than 35 in which the IGM has sequenced the whole genome, exome and/or transcriptome of children with cancer.  The researchers are in the process of writing a paper describing the variants, which they hope to publish later this year.

As with the 18-year-old, “the sequencing allows treating physicians to consider alternative drugs to treat each patient in the near or long term,” Dr. Mardis says. “The information may not identify a specific drug, but it can be used to help predict a specific drug target, helping narrow the choices.”

In addition to brain cancers, the IGM is now sequencing patients with sarcomas, acute lymphoma and more cancers.

Citation:  Miller KE, Kelly B, Fitch JH, Ross N, Avenarius MR, Varga E, Koboldt DC, Boue DR, Magrini V, Bocen SL, Finlay JL, Cottrell CE, White P, Gastier-Foster JM, Wilson RK, Leonard J, Mardis ER. Genome sequencing identifies somatic BRAF duplication c.1794_1796dupTAC;p.Thr599du in pediatric patient with low-grade ganglioglioma. Molecular Case Studies. 2018 Feb 6. pii: mcs.a002618. [Epub ahead of print]

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