Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease

Abstract

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 MPEB, 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.

When a dermatopathologist encounters the ultra‐rare: A case series of superficial soft tissue/cutaneous myxopapillary ependymomas

“…MPEs constitute a distinct class of ependymoma, as shown by methylome analysis studies 2,3,40 . Witt et al studied 122 ependymal tumors, showing that all tumors morphologically diagnosed as MPEs clustered to the “ependymoma, myxopapillary” category.…”

“…The possibility of two distinct types of MPE was further explored in a study of 185 MPEs, which demonstrated a subset of tumors in younger patients with predominantly papillary morphology, characterized by MGMT promoter hypermethylation, increased copy number alterations and aggressive clinical course. A second subset of tumors with significantly better clinical outcomes, despite their tanycytic morphology and greater cellular pleomorphism, was identified in older patients 40 . Data from next‐generation sequencing (NGS) studies are limited.…”

“…A second subset of tumors with significantly better clinical outcomes, despite their tanycytic morphology and greater cellular pleomorphism, was identified in older patients. 40 Data from next-generation sequencing (NGS) studies are limited. NGS analysis using a 324-gene DNA panel and an 86-gene RNA panel in a case of MPE with anaplastic transformation did not demonstrate any mutations in known cancer-related genes or pathogenic gene fusions, respectively.…”

Cauda Equina Neuroendocrine Tumors

“…HOXB13 is highly expressed in the tail bud of the developing embryo; in adults, it is most highly expressed in the mature prostate, where it is implicated in tumor development, 12,13 and in distal colonic mucosa. It has been localized with strong staining in myxopapillary ependymomas 11,14 that are clearly unrelated tumors. While it has not been found in PGLs at other sites, its expression in other NETs remains to be clarified.…”

Bromodomain and Extra-Terminal Protein Inhibitors: Biologic Insights and Therapeutic Potential in Pediatric Brain Tumors

“…Spinal ependymomas are made up of SP-sub-ependymoma, SP myxopapillary ependymoma, and SP ependymoma. A recent study by Bockmayr et al demonstrated that SP myxopapillary ependymoma is molecularly comprised of two distinct subgroups, MPE-A and MPE-B; with the former being associated with significantly higher relapse rate and decreased progression-free survival [91].…”