Genomic characterization of therapeutically-relevant targets in progressive/ high-grade meningioma

• Applicant: Professor Dr. Tareq Juratli
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: Funded in 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401837860

• Final Report Year: 2019

Final Report Abstract

To test the hypothesis that recurrent progressive meningiomas harbor specific genomic alterations driving their clinical behavior, we proposed to identify specific genomic events that are candidate determinants for meningioma grade and post-treatment progression. Interestingly, while the female predominance in WHO grade I meningiomas is widely appreciated, it is also recognized that males have a tendency for more biologically aggressive tumors. The mechanisms by which sex can affect meningioma grade and growth are not fully understood yet. In our comprehensive genomic profiling of progressive/ highgrade meningiomas, we discovered genomic alterations on the sex chromosomes that could partly explain these phenomena. Notably, due to the difficulties of normalization and segmentation, the sex chromosomes have been typically excluded from copy number analyses of previous meningioma studies. Using Whole-exome sequencing, we detected frequent inactivation of the X-linked dystrophin-encoding and muscular dystrophy-associated (DMD) gene, as well as the emergence of genetic alterations in several known X-linked tumor-suppressor genes that occur in cancers with a skewed gender distribution toward male patients, including: KDM6A in T-cell acute lymphoblastic leukemia, DDX3X in medulloblastomas, and STAG2 in myeloid and CNS neoplasms. Furthermore, we identified novel TERT gene translocations in meningiomas, often of higher WHO grade, with a dramatic impact on time-to-recurrence and survival. Most importantly, DMD inactivation was independent of all other alterations, in predicting unfavorable outcomes in progressive/higher-grade meningiomas. Thus, stratification for DMD inactivation can improve the design of progressive meningioma clinical trials and help improve patient management. In summary, my project has been successful in answering the proposed aims by identifying several genomic events that are candidate determinants for progression in meningiomas. Our findings have implications for understanding the biology of progressive meningiomas.

Publications

• DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome. Acta Neuropathol. 2018 Nov;136(5):779-792
  Juratli TA, McCabe D, Nayyar N, Williams EA, Silverman IM, Tummala SS, Fink AL, Baig A, Martinez-Lage M, Selig MK, Bihun IV, Shankar GM, Penson T, Lastrapes M, Daubner D, Meinhardt M, Hennig S, Kaplan AB, Fujio S, Kuter BM, Bertalan MS, Miller JJ, Batten JM, Ely HA, Christiansen J, Baretton GB, Stemmer-Rachamimov AO, Santagata S, Rivera MN, Barker FG 2nd, Schackert G, Wakimoto H, Iafrate AJ, Carter SL, Cahill DP, Brastianos PK
  
• Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum Meningiomas. J Neurol Surg B. 2019
  Williams, SR; Juratli, TA; Castro, BA.; Lazaro, TT.; Gill, C.; Nayyar, N; Strickland, MR; Babinski, M.; Johnstone, SE; Frosch, MP; Silverman, IM; Ely, HA; Kaplan, AB; D'Andrea, MR; Bihun, IV.; Hoang, K; Batchelor, E; Christiansen, J ; Cahill, DP.; Barker, FG.; Brastianos, PK