Heterogeneity within the PF-EPN-B ependymoma subgroup

Abstract

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.

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…This may indicate further rare molecular classes of ependymal tumours not yet established as methylation classes of their own and the requirement for further improvement of DNA methylation‐based classification. For PFA and PFB ependymomas large cohort studies have recently proposed further sub‐classification . For PFA ependymoma, nine subclasses have been identified that differ with respect to age at diagnosis, gender ratio, outcome, and/or frequencies of genetic alterations .…”

“…For PFA ependymoma, nine subclasses have been identified that differ with respect to age at diagnosis, gender ratio, outcome, and/or frequencies of genetic alterations . For PFB, five subclasses have been proposed that also harbour distinct demographics, copy number alterations and gene expression profiles . For the other ependymoma classes no subclasses have yet been identified.…”

“…For diagnostic copy number analysis , the most relevant feature among PF ependymomas to date is likely the presence of chromosome 1q gain as a strong negative prognostic factor . Recent data indicate that chromosome 1q gain may only be of prognostic relevance for PFA ependymomas and is enriched in the DNA methylation subclass PFA‐1c that is the subclass with the worst outcome . In addition, the six main ependymoma methylation classes have characteristic chromosomal patterns .…”

Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost

“…Indeed, this represents a major shift over the past decade, during which the majority of children aged <3 years were treated with RT‐sparing approaches; only recently has conformal RT to the tumor bed become the standard of care in North America . Recently, it has been shown that childhood posterior fossa ependymoma (PFE) is not a single entity but rather is comprised of at least 2 distinct molecular variants, group A (PFA) and group B (PFB), with distinct epigenetics, demographics, and outcomes . Although PFA represents nearly all infants with posterior fossa ependymoma, PFB is prevalent in adults and with a near equal distribution in adolescence .…”

“…3 Recently, it has been shown that childhood posterior fossa ependymoma (PFE) is not a single entity but rather is comprised of at least 2 distinct molecular variants, group A (PFA) and group B (PFB), with distinct epigenetics, demographics, and outcomes. 4 Although PFA represents nearly all infants with Cancer June 1, 2019 posterior fossa ependymoma, PFB is prevalent in adults and with a near equal distribution in adolescence. [5][6][7][8][9] A recent retrospective study across 820 cases of PFE has shown that the molecular subgroup is the most powerful predictor of outcome, and even within the PFA group, upfront postsurgical external-beam RT and a complete surgical resection are reported to be strong predictors of a good outcome.…”