Oh MG.

Top Line: We’re in an historic era of molecular classification of brain tumors, but we currently still rely on histological grading for meningiomas. 

The Study: This study introduces four consensus molecular subgroups of meningioma. Tissue from 121 meningiomas, enriched with high grade tumors, were used to define molecular subgroups while 80 additional tumors were used to assess applicability to clinical practice. They identified 4 distinct molecular groups, termed MG1 through MG4. MG1 or “immunogenic” tumors are characterized by immune infiltration and enrichment of immune regulation and signalling pathways. These tumors were also almost exclusively WHO grade 1 or 2 and NF2-mutated. In contrast, MG4 or “proliferative” tumors showed downregulation of immune signalling and upregulation of cell cycle signalling via proliferative transcription factors and protein complexes. MG4 proliferative tumors also had a much higher mutational burden than the other MG’s. MG3 or “hypermetabolic” tumors are enriched for several pathways involved in nucleotide and lipid metabolism. MG3 and MG4 tumors were more likely to be higher grade meningiomas. Finally, MG2 or “benign NF2 wild type” tumors are enriched for vascular and angiogenic pathways and rarely have NF2 mutation. There were two distinct subgroups of MG2 tumors characterized by either 1) specific gene mutations without chromosomal aberrations or 2) no driver mutations but consistent chromosomal polysomies.  Moving from MG1 through MG4 showed a progressive increase in genomic instability and the overall extent of molecular alterations. Importantly, the subgroups were derived from a strictly molecular approach without accounting for clinical behavior. Nevertheless, MG’s significantly correlated with clinical outcomes with MG1 through MG4 having the best to worst clinical outcomes with distinct separation on a Kaplan Meier curve of time to recurrence. Finally, MG was associated with time to recurrence independent of grade, extent of surgery, and adjuvant radiation.

TBL: Meningiomas can be classified into 4 distinct molecular groups that predict clinical behavior and may one day influence clinical management. | Nassiri, Nature 2021