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p16 Loss and E2F/cell cycle deregulation in infant posterior fossa ependymoma
Seth C Lummus1,2, Andrew M Donson2,3, Katherine Gowan3
1Department of Pathology, The University of Colorado School of Medicine, Aurora, Colorado.
Insights
Infant posterior fossa ependymomas (iEPN-PF) have poorer outcomes due to aggressive biology, specifically p16 loss, not treatment differences. This suggests CDK4/6 inhibitors as a potential therapy for iEPN-PF.
Area of Science:
- Pediatric neuro-oncology
- Molecular pathology
- Cancer genomics
Background:
- Infant posterior fossa ependymomas (iEPN-PF) exhibit poorer clinical outcomes compared to older children.
- Radiation therapy, a standard treatment for older patients, is withheld in infants due to neurotoxicity concerns.
- The reasons for the adverse outcomes in iEPN-PF remain unclear, with debate on whether it stems from treatment disparities or inherent biological aggressiveness.
Purpose of the Study:
- To investigate the molecular characteristics of iEPN-PF to determine if biological differences contribute to their poor prognosis.
- To compare the molecular profiles of iEPN-PF with those of ependymomas in older children.
Main Methods:
- Transcriptomic analysis and Fluorescence In Situ Hybridization (FISH) were performed on six anaplastic iEPN-PF samples.
- Samples were analyzed for p16 loss and 1q gains, and compared to anaplastic PF EPNs from older children.
- Immunohistochemistry (IHC) was used for validation of transcriptomic and FISH findings.
Main Results:
- All iEPN-PF samples belonged to the EPN PF subgroup A (PFA).
- Gene set enrichment analysis revealed enrichment of E2F targets and G2M checkpoint pathways in iEPN-PF.
- p16 loss and low p16 protein expression were identified as hallmarks of iEPN-PF, with no 1q gains observed. Higher mitotic rates were confirmed by MIB-1 IHC.
Conclusions:
- Biological differences, including p16 loss and deregulated E2F pathway activity, characterize iEPN-PF and likely contribute to their poor outcomes.
- The observed biological features suggest that the adverse prognosis is not solely due to the withholding of radiation therapy.
- Targeting the cyclin-dependent kinase 4/6 (CDK4/6) pathway with inhibitors presents a potential therapeutic strategy for iEPN-PF.
Background:
Posterior fossa (PF) ependymomas (EPNs) in infants less than 1 year of age (iEPN-PF) have a poorer clinical outcome than EPNs in older children. While radiation therapy is the standard of care for the latter, it is withheld in infants to avoid neurotoxicity to immature brain. It is unknown whether the adverse outcome in iEPN-PFs is due to treatment differences or aggressive biology. We examined this question using molecular profiling.
Methods:
Six anaplastic iEPN-PFs were subjected to transcriptomic analysis and FISH for p16 loss and gains of 1q, and compared with anaplastic PF EPNs from older children. Results were validated by immunohistochemistry (IHC).
Results:
All six iEPN-PFs were grouped within EPN PF subgroup A (PFA). E2F targets and G2M checkpoint were identified as the most enriched gene sets in iEPN-PF, which was validated in a larger independent cohort. Accordingly, MIB-1 IHC demonstrated a higher mitotic rate in iEPN-PFs than noninfant anaplastic EPN PFA. Genetic and protein analyses demonstrated that p16 loss and low p16 protein expression is a hallmark of iEPN-PF, and that none harbored 1q gains. Kaplan-Meier analysis confirmed the poorer clinical outcome of the iEPN-PF cohort.
Conclusions:
Biological differences, characterized by loss of p16 expression without gains of 1q in iEPN-PFs, as well as deregulated E2F target gene transcription, are indicative of deregulated p16-CDK4/6-pRB-E2F pathway activity. This may underlie the poor clinical outcome seen in this group of iEPN-PFs, rather than the withholding of radiation therapy. Results suggest a potential actionable therapy for iEPN-PF, namely cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.
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