Authors: Joshua N. Loewenstern; Will Shuman; Remi Kessler; Karan Kohli; Margaret Pain, MD; Melissa Umphlett, MD; Robert Sebra, PhD; Michael Donovan, MD, PhD; Joshua Bederson, MD; Mary Fowkes, MD, PhD; Raj Shrivastava, MD (New York, NY)

Introduction: While most resected low-grade meningiomas will not recur, there exists a significant population of more aggressive recurrent low-grade and atypical/anaplastic meningiomas that are likely to recur after surgical resection, leading to increased morbidity, re-operation, and decreased survival. However, few studies have investigated genetic risk factors driving meningioma recurrence. The present study aimed to identify key driver mutations that are associated with post-resection outcomes. Methods: 150 consecutively resected recurrent low-grade (WHO grade I, n=32) and high-grade (WHO grade II/III, n=118) meningiomas with adequate biopsy specimens from 2007-2016 underwent complete genomic sequencing and assessed for driver mutations. Genetic variants were correlated with post-operative clinical outcomes including tumor recurrence, functional status, and progression-free survival (PFS). Results: The most common driver mutations identified included ARID1A , CDKN2A , NF1 , NF2 , NOTCH3 , PTCH1 , and SMARCB1 , which combined were present in 55% of meningiomas. Tumors with a NOTCH3 driver mutation had decreased PFS (HR=1.95, p=0.047). Further, tumors without a known driver mutation had improved PFS relative to those with at least 1 identified driver mutation (p=0.042), but those with multiple driver mutations did not differ from those with 1 mutation (p=0.75). Meningiomas with a NF2 mutation were associated with larger tumor size (p=0.039) and correlated with higher mitotic proliferation on histopathological examination (p=0.003). Conclusion: Genetic variants involved in intercellular signaling, cell differentiation, and cytoskeletal integrity like NOTCH3 and NF2 may be especially predictive of recurrence risk and tumor proliferation. Identification of driver mutations associated with recurrence and post-operative outcomes is an important step in targeted molecular treatment of tumors refractory to resection and radiation.
Integra Foundation Award