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Abstract
Abstract Introduction: Ependymomas (EPNs), accounting for 5-6% of glial tumors, arise from radial glial cells and exhibit significant heterogeneity, leading to variable prognosis. Despite their clinical significance, the oncogenic drivers and potential therapeutic targets for EPNs remain poorly understood. Long non-coding RNAs (lncRNAs) are emerging as crucial regulators in many cancers, influencing tumorigenesis and therapeutic resistance. However, their role in EPN pathobiology has not been explored. This study aims to unravel the lncRNA landscape in EPNs to identify novel diagnostic biomarkers and therapeutic targets, improving patient stratification and treatment outcomes. Methods: 38 EPN tumor samples were classified into 21 supratentorial (ST), 13 posterior fossa (PF), and 4 spinal (SP) subtypes based on WHO 2021 criteria and subjected to RNA sequencing to map their RNA landscape, using 6 normal brain tissue samples as control. Raw data was normalized to identify significantly deregulated genes (padj < 0.05, -1 ≤ log2 fold change ≥ 1). qPCR validated the top deregulated lncRNAs (n = 60 extended cohort, p < 0.05). Pan-cancer analysis, functional annotation, target prediction, co-expression network construction, and prognostic relevance were assessed using ECORI, LncExplore, LncHub2, RNAInter, and Prognoscan respectively. Results: RNA sequencing identified 2, 271 upregulated and 1, 728 downregulated lncRNAs in EPN sub-groups, with 108 commonly upregulated and 187 downregulated across subtypes. qPCR confirmed LINC01971 overexpression in ST-EPNs (p < 0.001), FAM74A7 upregulation in PF and SP subtypes (p < 0.0001, p < 0.001), and LINC00320 downregulation in all subgroups (p < 0.001). Pan-cancer analysis revealed high LINC01971 in uterine endometrial and lung carcinoma, slightly increased FAM74A7 in kidney clear cell carcinoma, and low LINC00320 across all cancers. LINC01971, co-expressed with RELA, is involved in NF-kB-driven tumorigenesis and immune modulation. Pathway analysis associated with transcription factors (ESR1, SOX2, TP53, FOXA1) and chromatin modifiers (H3K27me3, H3K4me3), indicating a role in epigenetic reprogramming. FAM74A7, correlated with transcription factors (EOMES, SOX2, NANOG, FOXA1), is linked to tumor progression and epigenetic regulation, with disease associations (papillary, cellular, and myxopapillary EPNs) supporting its potential as a diagnostic and therapeutic target. LINC00320, reduced in malignant gliomas, regulates FOXA1 and H3K4me3, affecting metabolism and protein lipidation. Co-expression patterns in EPNs and gliomas highlight their role in tumor progression and neurodegenerative diseases Prognoscan links RELA, FOXA1, and SOX2 overexpression to poor prognosis in various cancers. This comprehensive transcriptomic analysis of EPNs unveils novel lncRNAs, as potential prognostic biomarkers and therapeutic targets. Citation Format: Rafat Malik, Dr. Amandeep Kumar, Dr. Vaishali Suri, Dr. Mehar Chand Sharma. Characterization of long non-coding RNAs in ependymomas: Uncovering potential biomarkers and therapeutic targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3309.
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