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Genomic Studies Reveal New Recurrently Mutated Genes in Meningioma

NEW YORK (GenomeWeb News) – Two studies published this week are offering a look at the genetics behind meningioma, a type of primary central nervous system tumor.

In Nature Genetics, a Boston-based research team did whole-genome or whole-exome sequencing on matched tumor-normal samples from 17 individuals with meningioma, followed by targeted sequencing of suspicious genes in four-dozen more meningioma tumors.

Along with mutations in genes linked to meningioma in the past — such as the neurofibromin 2 gene NF2 — the researchers uncovered previously undetected somatic changes in new genes, including the PI3K-AKT-mTOR pathway gene AKT1 and SMO, a gene coding for a component of the Hedgehog signaling pathway.

Those two genes were recurrently mutated amongst tumors lacking NF2 mutations, they noted, and appear to be promising targets for new meningioma therapies.

"The wonderful thing about those mutations is that there are already drugs in the clinic to target cancers with those mutations," co-corresponding author Rameen Beroukhim, an oncology researcher affiliated with the Dana-Farber Cancer Institute, the Broad Institute, and Harvard Medical School, noted in a statement.

In the journal Science, meanwhile, an international team led by investigators at Yale University used a combination of genotyping, exome sequencing, and/or targeted gene sequencing to detect mutations, rearrangements, and copy number changes in tumors from 300 meningioma patients. As in the first study, that group picked up NF2, AKT1, and SMO gene mutations. But its findings also pointed to recurrent mutations in two more genes: KLF4 and TRAF7.

Within groups of tumors carrying mutations to each of the five most commonly mutated meningioma genes, the researchers saw differences in meningioma location in the brain and propensity for becoming cancerous.

"Combining knowledge of these mutations with the location of tumor growth has direct clinical relevance and opens the door for personalized therapies," senior author Murat Günel, a genetics and neurobiology researcher at Yale School of Medicine, said in a statement.

Meningioma tumors develop in the meninges membrane that envelops the brain. Though many grow slowly and/or are benign, roughly 10 percent eventually become malignant. Not only the cancerous forms of the condition are a concern, though, since benign tumors sometimes begin growing aggressively and become very large, leading to complications such as seizures or even death.

Past research has shown that up to half of meningiomas involve mutations to a tumor suppressor-coding gene called NF2. But the complete suite of genetic changes that can contribute to the condition has not been determined.

Consequently, researchers are keen to delve into meningioma genomes in more detail, both to better understand the biology behind the disease and to come up with therapies to deal with the tumors, which are currently treated via a combination of surgery and radiation, when possible.

For their part, Beroukhim and his colleagues used Illumina's HiSeq 2000 to do whole-genome sequencing on tumor-normal pairs from 11 individuals with meningioma. On the exome sequencing side, they sequenced samples from half a dozen other individuals, capturing coding sequences with Nimblegen or Agilent arrays prior to sequencing.

As expected, many of the tumors contained alterations affecting NF2. But the team picked up other recurrent mutations as well. For instance, 8 percent of the meningioma sequences included mutations to genes involved in epigenetic processes, such as the chromatin remodeling-related gene SMARCB1 or the histone demethylase genes KDM6A and KDM5C.

While the overall rate of mutation, copy number change, or rearrangement was fairly low in the tumors tested, a few of the meningiomas had massively rearranged genomes consistent with chromothripsis. Losses involving bits of chromosome 22 were common, too, turning up mainly in the NF2-mutated samples.

In addition, within tumors lacking NF2 mutations, the researchers detected a jump in mutations in two other genes: SMO and AKT1. Alterations in these genes appeared to bump up the activity of the Hedgehog signaling and PI3 kinase-AKT-mTOR pathways in which SMO and AKT1 participate, respectively.

Based on their data so far, the team estimated that mutations in Hedgehog or PI3K-AKT-mTOR pathways act as drivers in around 15 percent of meningiomas.

"These mutations were present in therapeutically challenging tumors of the skull base and higher grade," Beroukhim and his co-authors noted. "These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets."

In the study conducted by Yale's Günel and co-investigators the researchers assessed 50 tumor-normal sets by exome sequencing and genome-wide genotyping. The most promising genes identified from that discovery set data were then tested in 250 more meningioma samples via targeted sequencing and copy number analyses.

All told, that team saw chromosome 22 losses in just under half of the meningioma cases and NF2 mutations in more than one-third of the tumors. A subset of the tumors lacking NF2 mutations carried alterations in an apoptosis promoting gene called TRAF7 or the transcription factor KLF4.

As in the Nature Genetics study, researchers identified SMO and AKT1 in a subset of the meningiomas. Again, SMO glitches coincided with enhanced Hedgehog signaling, though the Yale researchers and their colleagues saw somewhat distinct relationships between tumor mutations, location, and aggressiveness.

"These results clearly identify meningioma subgroups," Günel and his co-authors wrote, "distinguishing them based on their mutually exclusive distribution of mutations, distinct potential for chromosomal instability and malignancy, anatomical location, histological appearance, gene expression, and acetylation pattern."

"Our results show that the mutational profile of a meningioma can largely be predicted based on its anatomical position," they added, "which in turn may predict likely drug response."

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