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Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology

ABSTRACT: Posterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell dense tumor areas. To determine molecular differences between these morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Inter alia, DNA methylation profiles were analysed for high and low cell density regions seperately in 21 cases. Tumor areas with low and high cell density showed diverging DNA methylation profiles regarding their similarity to distinct previously discovered PF-EPN-A subtypes in 9/21 cases. Prognostically relevant chromosomal changes at 1q and 6q showed spatial heterogeneity within single tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248618 | GEO | 2024/01/31

REPOSITORIES: GEO

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Project description:Ependymomas are neuroepithelial tumors of the central nervous system (CNS), presenting in both adults and children but accounting for almost 10% of all pediatric CNS tumors and up to 30% of CNS tumors in children under 3 years (Bouffet et al., 2009; McGuire et al., 2009; Rodriguez et al., 2009). In children, most ependymomas arise in the posterior fossa, while most adult ependymomas present around the lower spinal cord and spinal nerve roots. Ependymomas display a wide range of morphological features, and several variants are listed in the World Health Organization (WHO) classification (Ellison et al., 2016). These variants are assigned to three WHO grades (I-III), but the clinical utility of this classification is acknowledged to be limited (Ellison et al., 2011). An increasing understanding of the genomic landscape of ependymoma and the discovery of distinct molecular groups by DNA methylation or gene expression profiling have begun to refine approaches to disease classification and prognostication, but have yet to be translated into clinical routine (Hoffman et al., 2014; Mack et al., 2014; Pajtler et al., 2017; Pajtler et al., 2015; Parker et al., 2014; Wani et al., 2012; Witt et al., 2011). Our comprehensive study of DNA methylation profiling across the entire disease demonstrated three molecular groups for each major anatomic compartment: supratentorial (ST), posterior fossa (PF), and spinal (SP) (Pajtler et al., 2015). In the ST compartment, two molecular groups (ST-EPN-RELA and ST-EPN-YAP1) align with tumors harboring specific genetic alterations, RELA and YAP1 fusion genes, which were initially discovered in a whole genome sequencing study (Parker et al., 2014). Among PF ependymomas, two of three molecular groups, PFA (PF-EPN-A) and PFB (PF-EPN-B), account for nearly all tumors; PF-SE tumors are rare, generally showing the morphology of a subependymoma (Pajtler et al., 2015). PFA tumors are found mainly in infants and young children (median age ≈ 3yrs) and have a relatively poor outcome, while PFB tumors are generally found in young adults (median age ≈ 30yrs) and are associated with a better prognosis (Pajtler et al., 2015; Witt et al., 2011). PFA tumors show few copy number alterations (CNAs), while PFB tumors harbor multiple CNAs that tend to affect entire chromosomes. While recurrent structural variants (SVs) are found in ST ependymomas, recurrent SVs or other mutations, such as single nucleotide variants (SNVs) and insertions or deletions (indels), have not been identified in PF ependymomas to date (Mack et al., 2014; Parker et al., 2014).

Project description:Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

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Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology

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