Artikel
DMD genomic deletions characterise a subset of progressive/higher-grade meningiomas with poor outcome
DMD Gendeletionen sind häufige genomische Ereignisse in progressiven und anaplastischen Meningeome
Suche in Medline nach
Autoren
-
Tareq Juratli
- Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Klinik für Neurochirurgie, Dresden, Deutschland; Massachusetts General Hospital, Division of Neuro-Oncology and Hematology/Oncology, Departments of Medicine and Neurology, Boston, MA, United States; Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, United States
-
Devin McCabe
- Broad Institute of Harvard and MIT, Boston, MA, United States
-
Erik Willimas
- Massachusetts General Hospital, Department of Pathology, Boston, MA, United States
-
Maria Martinez-Lage
- Massachusetts General Hospital, Department of Pathology, Boston, MA, United States
-
Ganesh Shankar
- Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, United States
-
Matthias Meinhardt
- Medizinische Fakultät Carl Gustav Carus, Institut für Pathologie, Dresden, Deutschland
-
Gustavo Baretton
- Medizinische Fakultät Carl Gustav Carus, Institut für Pathologie, Dresden, Deutschland
-
Hiroaki Wakimoto
- Massachusetts General Hospital, Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Boston, MA, United States
-
Scott Carter
- Broad Institute of Harvard and MIT, Boston, MA, United States
-
Daniel Cahill
- Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, United States
-
Priscilla Brastianos
- Massachusetts General Hospital, Division of Neuro-Oncology and Hematology/Oncology, Departments of Medicine and Neurology, Boston, MA, United States
| Veröffentlicht: | 8. Mai 2019 |
|---|
Gliederung
Text
Objective: 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.
Methods: We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples.
Results: 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%). 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.
Conclusion: We discovered novel and frequently acquired genomic alterations on the sex chromosomes in addition to TERT rearrangements during progression in high-grade meningioma. DMD inactivation and TERT alterations identify a subset of progressive/high-grade meningiomas with worse outcomes. Thus, stratification for both genomic alterations can improve the design of progressive meningioma clinical trials and help improve patient management.
