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Aggressive Meningioma Linked to Transcription Factor Activity

NEW YORK (GenomeWeb) – A new integrated 'omics analysis suggests that the transcription factor FOXM1 can act as a meningioma driver, prompting proliferation, progression, and relatively poor outcomes in individuals with the disease, a primary central nervous system tumor that forms in meninges tissue surrounding the brain and spinal cord.

As they reported online today in Cell Reports, researchers from the University of California, San Francisco and California State University Channel Islands used a combination of RNA sequencing, exome sequencing, array-based methylation profiling, and other approaches to retrospectively search for molecular drivers in 280 tumor samples from 261 individuals with meningioma.

Based on the transcriptomic patterns present in meningioma cases with poorer clinical outcomes, the team concluded that FOXM1 activation and downstream signaling appear to prompt more aggressive forms of meningioma.

"We now need to find out what other genes FOXM1 is activating to drive meningioma growth, and block those targets with clinical therapies," senior author David Raleigh, a radiation oncology and neurological surgery researcher at UCSF, said in a statement.

The majority of meningiomas are benign and can be successfully treated using surgery and radiation, the team explained. But these interventions are far less likely to be effective over the long term in individuals with high-grade tumors and especially aggressive forms of the disease.

"There haven't been as many studies on what drives 'problem' meningiomas," Raleigh said. "For clinicians, patients, and families, these are the most heartbreaking cases because we expect to cure meningiomas, but sometimes we can't and we don't always do a good job of differentiating 'good' and 'bad' meningiomas ahead of time."

With that in mind, he and his colleagues set out to characterize a large set of meningioma tumors, searching for features that marked the most worrisome cases. The researchers focused on 280 tumors collected through UCSF's Brain Tumor SPORE Biospecimen Core from 1990 to 2015 — a set in which high-grade or recurrent meningioma tumors were reportedly overrepresented.

The team profiled the fresh-frozen or formalin-fixed, paraffin-embedded samples with RNA sequencing, exome sequencing, array-based DNA methylation profiling, immunohistochemistry, NanoString technology-based targeted gene expression testing, and chromatin immunoprecipitation sequencing. Matched normal samples were subjected to exome sequencing for a subset of two dozen aggressive meningioma cases.

Along with corresponding clinical outcome data, the profiles made it possible to narrow in on a cluster of aggressive tumors with higher-than-usual FOXM1 expression. Another tumor cluster represented high-grade tumors that were more common in men and contained alterations involving genes from metabolic or oxidative phosphorylation pathways.

Most transcriptional clusters did not show significant ties to clinical outcomes, the researchers reported. But their data did uncover a trend toward lower-than-usual rates of local recurrence-free survival or overall survival times in tumors with enhanced expression of FOXM1 or its targets, which also tended to be more prone to cell proliferation, hypermethylation, Wnt pathway signaling, and aggressiveness.

"The identification of FOXM1 as a master transcription factor for meningioma proliferation provides a potential molecular target with prognostic and therapeutic significance," Raleigh and co-authors wrote, noting that FOXM1 expression may help in distinguishing meningioma cases that might benefit from more aggressive treatment and adjuvant therapy.