GRCh38 · COSMIC v96


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DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome.
Paper ID
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, Schackert G, Wakimoto H, Iafrate AJ, Carter SL, Cahill DP and Brastianos PK
Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Acta neuropathologica, 2018
ISSN: 1432-0533
PMID: 30123936 (view at PubMed or Europe PMC)
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.
Paper Status