Transcriptional profiling of paediatric ependymomas identifies prognostically significant groups

Area of Science:

• Pediatric neuro-oncology
• Molecular diagnostics
• Cancer genomics

Background:

• Supratentorial ependymomas often harbor oncogenic fusions (ZFTA-RELA, YAP1-MAMLD1), unlike posterior fossa (PF) ependymomas which lack recurrent mutations.
• PF ependymomas are molecularly classified into group A (PFA) and group B (PFB) based on gene expression or methylation.

Purpose of the Study:

• To apply NanoString nCounter Technology for molecular subtyping of pediatric ependymomas.
• To identify distinct molecular groups within supratentorial and PF ependymomas using signature genes.
• To correlate molecular subgroups with genetic fusions and clinical outcomes.

Main Methods:

• NanoString nCounter Technology was used to analyze 16 supratentorial and 50 PF pediatric ependymomas.
• Clustering analysis based on 4-5 group-specific signature genes identified molecular subgroups.
• Next-generation sequencing confirmed genetic fusions (ZFTA-RELA, YAP1-MAMLD1, ZFTA-MAML2).

Main Results:

• NanoString identified RELA fusion-positive (RELA+) and YAP1 fusion-positive (YAP1+) signatures in supratentorial tumors, correlating with ZFTA-RELA and YAP1-MAMLD1 fusions respectively.
• PF tumors were classified into PFA (42 samples) and PFB (7 samples) groups, consistent with prior findings.
• Eight out of nine patients with the RELA+ signature survived over 5 years, suggesting potential prognostic value.

Conclusions:

• The NanoString method serves as a single, effective tool for diagnosing all four main molecular groups of ependymoma.
• The ZFTA-RELA fusion is a key molecular marker in a subset of pediatric ependymomas.
• Further clinical investigation into survival differences among molecular groups, particularly ZFTA-RELA positive cases, is warranted.