DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome.

Abstract

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.

• Authors: Tareq A Juratli, Devin McCabe, Naema Nayyar, Erik A Williams, Ian M Silverman, Shilpa S Tummala, Alexandria L Fink, Aymen Baig, Maria Martinez-Lage, Martin K Selig, Ivanna V Bihun, Ganesh M Shankar, Tristan Penson, Matthew Lastrapes, Dirk Daubner, Matthias Meinhardt, Silke Hennig, Alexander B Kaplan, Shingo Fujio, Benjamin M Kuter, Mia S Bertalan, Julie J Miller, Julie M Batten, Heather A Ely, Jason Christiansen, Gustavo B Baretton, Anat O Stemmer-Rachamimov, Sandro Santagata, Miguel N Rivera, Fred G Barker 2nd, Gabriele Schackert, Hiroaki Wakimoto, A John Iafrate, Scott L Carter, Daniel P Cahill, Priscilla K Brastianos
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 136 Issue 5 Pg. 779-792 (11 2018) ISSN: 1432-0533 [Electronic] Germany
• PMID: 30123936 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DMD protein, human
• Dystrophin
• RNA, Messenger
• TERT protein, human
• Telomerase

Topics

• Aged
• Aged, 80 and over
• Cell Line, Tumor (pathology, ultrastructure)
• Cohort Studies
• Disease Progression
• Dystrophin (genetics, metabolism)
• Female
• Gene Deletion
• Humans
• Magnetic Resonance Imaging
• Male
• Meningeal Neoplasms (diagnostic imaging, genetics, pathology)
• Meningioma (diagnostic imaging, genetics, pathology)
• Microscopy, Electron, Transmission
• Middle Aged
• Multiplex Polymerase Chain Reaction
• RNA, Messenger (metabolism)
• Sex Chromatin (genetics)
• Telomerase (genetics, metabolism)
• Exome Sequencing