PATH-64. UNDERSTANDING MECHANISTIC UNDERPINNINGS OF MOLECULAR SUBGROUPS OF MENINGIOMA

Abstract Meningiomas are the most common intracranial tumors. In the past, they were thought to be indolent and could be treated by resection. The current standard of care utilizes WHO histopathological grading to identify malignant potential. Our lab identified three molecular groups (MenG A, B, and C) using CNVs, methylation, and/or expression profiling with different biological characteristics. These groups were independently validated and predicted recurrence more reliably than WHO grade. MenG A is genomically stable but harbors tumors with point mutations, mainly in TRAF7, KLF4, and AKT1. On the other hand, MenG B and C tumors have chromosome 22q arm deletion or loss of merlin, the protein product of the NF2 gene. Moreover, MenG B is characterized by DNA hypomethylation, while MenG C tumors show DNA hypermethylation and have additional chromosomal losses, most notably in chromosome 1p. Lastly, while MenG A/B are indolent, MenG C – comprising approximately 28% of meningiomas – recur frequently and are refractory to radiotherapy and/or surgery. How can two groups of tumors with the same driver mutation behave so differently? Hence, our lab is interested in (1) what molecular pathway/factor(s) are necessary for becoming any meningioma, and (2) what mechanisms are critical for the aggressiveness of MenG C. Here, we investigate the role of TRAF7 in meningioma biology. Toward this end, we study interactors, modulators, and individual mutations in cell culture. In addition, we use published exome sequencing and expression data to reveal possible connections between chromatin state and individual genes. In conclusion, a variety of underlying mechanisms drive meningioma tumorigenicity and aggressiveness. Elucidating these mechanisms could provide future therapeutic targets for currently untreatable meningiomas.