Heterogeneity within the PF-EPN-B ependymoma subgroup
- 762 Downloads
Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.
KeywordsEpendymoma Posterior fossa Subgrouping PFB PFA Clustering
VR is supported by operating funds from the Canadian Institutes of Health Research, American Brain Tumor Association, the Garron Family Cancer Center, Meagan’s Walk, b.r.a.i.n.child, the Brain Tumor Foundation of Canada and a Collaborative Ependymoma Research Network (CERN) basic science fellowship. FMGC is supported by the Stephen Buttrum Brain Tumor Research Fellowship, granted by Brain Tumor Foundation of Canada. MZ is supported by Garron Family Cancer Center Fellowship, Meagan’s Walk Neuro-Oncology Fellowship and Restracomp from Research Training Center at The Hospital for Sick Children. MDT is supported by funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, and operating funds from the National Institutes of Health (R01CA159859 and R01CA148699), and the Pediatric Brain Tumor Foundation. EB is supported by funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. KWP is supported by a CERN Research Fellowship.
- 1.Araki A, Chocholous M, Gojo J, Dorfer C, Czech T, Heinzl H et al (2016) Chromosome 1q gain and tenascin-C expression are candidate markers to define different risk groups in pediatric posterior fossa ependymoma. Acta Neuropathol Commun 4:88. https://doi.org/10.1186/s40478-016-0349-9 CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Gojo J, Lotsch D, Spiegl-Kreinecker S, Pajtler KW, Neumayer K, Korbel P et al (2017) Telomerase activation in posterior fossa group A ependymomas is associated with dismal prognosis and chromosome 1q gain. Neuro Oncol 19:1183–1194. https://doi.org/10.1093/neuonc/nox027 CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R et al (2013) Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 125:913–916. https://doi.org/10.1007/s00401-013-1126-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Kilday JP, Mitra B, Domerg C, Ward J, Andreiuolo F, Osteso-Ibanez T et al (2012) Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children’s Cancer Leukaemia Group (CCLG), Societe Francaise d’Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res 18:2001–2011. https://doi.org/10.1158/1078-0432.ccr-11-2489 CrossRefPubMedGoogle Scholar
- 14.Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F et al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743. https://doi.org/10.1016/j.ccell.2015.04.002 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW et al (2016) Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis. J Clin Oncol 34:2468–2477. https://doi.org/10.1200/jco.2015.65.7825 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Rand V, Prebble E, Ridley L, Howard M, Wei W, Brundler MA, Fee BE, Riggins GJ, Coyle B, Grundy RG (2008) Investigation of chromosome 1q reveals differential expression of members of the S100 family in clinical subgroups of intracranial paediatric ependymoma. Br J Cancer 99:1136–1143. https://doi.org/10.1038/sj.bjc.6604651 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Ward S, Harding B, Wilkins P, Harkness W, Hayward R, Darling JL, Thomas DG, Warr T (2001) Gain of 1q and loss of 22 are the most common changes detected by comparative genomic hybridisation in paediatric ependymoma. Genes Chromosomes Cancer 32:59–66. https://doi.org/10.1002/gcc.1167 CrossRefPubMedGoogle Scholar