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

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.

Juratli TA1,2,3, McCabe D4,5, Nayyar N2, Williams EA1,6, Silverman IM7, Tummala SS1, Fink AL1, Baig A6, Martinez-Lage M6, Selig MK6, Bihun IV2, Shankar GM1, Penson T1, Lastrapes M4,5, Daubner D8, Meinhardt M9, Hennig S3, Kaplan AB2, Fujio S1, Kuter BM2, Bertalan MS2, Miller JJ1, Batten JM6, Ely HA7, Christiansen J7, Baretton GB9, Stemmer-Rachamimov AO6, Santagata S10, Rivera MN6, Barker FG 2nd1, Schackert G3, Wakimoto H1, Iafrate AJ6, Carter SL4,5, Cahill DP1, Brastianos PK11.
Acta Neuropathol. 2018 Nov;136(5):779-792. doi: 10.1007/s00401-018-1899-7. Epub 2018 Aug 19.