Common Genetic Driver Linked to Aggressive Meningiomas

Researchers in California have uncovered molecular insights into the biology of meningioma that could lead to new treatment approaches with fewer side effects. In a study published online March 27, 2018, in Cell Reports, researchers identified genomic, epigenomic, and transcriptomic mechanisms that converge on a FOXM1/Wnt signaling axis in aggressive meningioma. The researchers theorize that the FOXM1/Wnt signaling axis is associated with meningioma cell proliferation and is a marker of poor clinical outcomes across molecular subgroups.

“We were surprised to find that a single transcription factor, FOXM1, was associated with all clinically-aggressive meningiomas from diverse patients of different demographic backgrounds,” said study investigator David R. Raleigh, MD, PhD, an Assistant Professor in the Departments of Radiation Oncology and Neurological Surgery at the University of California San Francisco, San Francisco.

Activation of the FOXM1 gene was found in the aggressive tumors from different regions around the brain or skull base, and consisted of many different grades, according to Raleigh. The researchers hope that finding a common genetic driver of aggressive meningiomas will help clinicians detect these cancers earlier and lead to new therapies aimed at curing these difficult-to-treat tumors. Even though most meningiomas are treatable with radiotherapy or surgery, approximately 20% are aggressive and recur after surgery and radiation therapy.

The researchers examined 280 human meningioma samples collected between 1990 and 2015. Using an array of techniques, including RNA sequencing and targeted gene expression profiling, they searched for links between gene activity and protein production in these tumors and the clinical outcomes of patients. The researchers found that heightened FOXM1 activity was the unifying factor between aggressive meningiomas in both men and women, in older and younger patients, and in meningiomas arising in different parts of the brain.

The study showed the gene’s activation was associated with newly diagnosed tumors as well as with tumor recurrence following treatment. The research team also looked at DNA methylation; they found significant hypermethylation in the most aggressive meningiomas, and these DNA modifications specifically silenced genes that usually inhibit FOXM1 expression and Wnt signaling.

“The discovery of FOXM1 as a key transcription factor for meningioma recurrence sheds light on potential targets for future molecular therapies to treat meningioma patients,” Raleigh told Cancer Network. “There are no effective systemic therapies for meningioma. Understanding meningioma biology not only tells us something about how these tumors grow, but gives us a hint about how we might block meningioma growth to improve outcomes and prolong survival.”

Raleigh said future treatments will need to do more than simply block FOXM1, noting that further study is needed to shed light on what additional genes FOXM1 is activating to drive meningioma growth.