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CNV-Adjusted Analysis Points to Prognostically Informative Meningioma Methylation Groups

NEW YORK – New research from a University of California at San Francisco-led team has identified three DNA methylation-based meningioma groups with an epigenetic profiling study that took into account other molecular features including copy number variant (CNV) profiles of the primary intracranial tumors.

"The data presented here demonstrate a need for DNA methylation profiling to stratify meningioma patients for molecular therapy," co-senior and co-corresponding author David Raleigh, a radiation oncology and neurological surgery researcher at UCSF, and his colleagues wrote. "Integrating genetic, epigenetic, transcriptomic, biochemical, proteomic, and single-cell approaches, we find meningiomas are composed of three DNA methylation groups with distinct clinical outcomes and biological drivers."

For a paper published in Nature Genetics on Monday, the researchers performed array-based methylation profiling on samples from 565 meningioma patients treated at two centers in the US and Hong Kong between the early 1990s and 2019, using a pipeline called SeSAMe to account for CNV effects on methylation before analyzing methylation data alongside targeted sequencing, exome sequencing, chromatin immunoprecipitation sequencing, transcriptomic and proteomic profiling, and other data on a subset of meningioma tumors.

"Our findings are supported by analyses in entirely independent discovery and consecutive validation cohorts from UCSF and the University of Hong Kong," Raleigh explained in an email.

The team's integrated molecular analyses highlighted Merlin-intact meningioma, immune-enriched meningioma, and the hypermitotic meningioma groups. Along with comparisons to methylation groups defined by analyses that did not take CNVs into account, the group investigated further with CRISPR-based gene editing and other functional experiments.

"[U]sing bioinformatic pipelines that account for the impact of CNVs on beta methylation detection, we identify three robust DNA methylation groups of meningiomas with distinct clinical outcomes, biological drivers, and therapeutic vulnerabilities," Raleigh wrote, adding that "ours is the first meningioma epigenetic study to validate all the bioinformatic groups we report using mechanistic and functional approaches across meningioma cells, organoids, xenografts, and patients."

In contrast to meningiomas arising in neurofibromatosis type 2 patients missing an NF2 gene coding for the Merlin tumor suppressor protein, the researchers found that more than one-third of the meningiomas fell into a Merlin-intact group with the most favorable clinical outcomes and vulnerability to cytotoxic therapy.

On the other hand, the team classified 28 percent of the tumors into a hypermitotic meningioma group linked to cytotoxic therapy resistance and poor outcomes. The remaining tumors — almost 40 percent of the meningioma set — fell into an immune-enriched group marked by immune cell infiltration, lymphatic vessel features, and intermediate survival outcomes.

With a series of follow-up analyses, the investigators saw signs that tumors classified into poor- or intermediate-outcome groups may be particularly apt to respond to cell cycle inhibitor treatments.

"These findings underscore the importance of DNA methylation profiling for meningioma patients, which (we anticipate) will ultimately allow for selection or enrollment of clinical trials of cell cycle inhibitors or other molecular therapies," Raleigh explained.

He and his coauthors emphasized the need for "careful consideration of meningioma DNA methylation groups in the context of available preclinical data, and WHO grade, when stratifying meningioma patients for new treatments," though they cautioned that the current results suggest that "DNA methylation grouping does not obviate the importance of meningioma grading."