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Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease
Michael Bockmayr1,2,3,4, Kim Harnisch5,6, Lara C Pohl1,2
1Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Background:
Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients' clinical course are unknown.
Methods:
We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPE-B, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors.
Results:
MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (P = 3.4e-06).
Conclusions:
We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
Insights
Myxopapillary ependymoma (MPE) is heterogeneous. Two molecular subtypes, MPE-A and MPE-B, identified by methylation profiling, show distinct clinical courses and outcomes, necessitating tailored treatment strategies.
Area of Science:
- Neuro-oncology
- Molecular pathology
- Genomics
Background:
- Myxopapillary ependymoma (MPE) exhibits significant heterogeneity in histopathology and patient outcomes.
- The molecular underpinnings of MPE and predictive markers for clinical course remain largely unknown.
Purpose of the Study:
- To investigate the molecular and clinical heterogeneity of Myxopapillary ependymoma.
- To identify distinct molecular subtypes of MPE and their association with clinical and pathological features.
Main Methods:
- DNA methylation profiling was performed on 185 MPE tumors to define subtypes.
- Copy number profiling, MGMT promoter methylation analysis, histomorphological evaluation, and RNA sequencing were conducted.
- Epidemiological, clinical, pathological, and molecular data were analyzed for associations with identified subtypes.
Main Results:
- Two molecular subtypes, MPE-A and MPE-B, were identified based on methylation profiling.
- MPE-A (median age 27) showed papillary morphology, MGMT hypermethylation, higher relapse rates (85% at 10 years), and copy number alterations.
- MPE-B (median age 45) included WHO grade II tumors with tanycytic morphology and a significantly better outcome (33% relapse at 10 years).
Conclusions:
- Two distinct molecular subtypes of MPE (MPE-A and MPE-B) were identified, explaining observed heterogeneity.
- These subtypes exhibit significant differences in progression-free survival, suggesting the need for distinct surveillance and treatment protocols.
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