Dipg-37. transcriptional, epigenetic, and immunological features of paediatric-type h3 k27-altered diffuse midline gliomas originating from different brain locations
Neuro-Oncology(2023)
摘要
Abstract Diffuse midline gliomas (DMG) are highly aggressive brain tumours predominantly affecting young children. The main oncogenic driver is the substitution of lysine 27 to methionine (K27M) in histone 3 (H3) or overexpression of EZHIP resulting in global loss of H3K27me3. Recent single-cell (epi-)genomic studies have identified developmentally-restricted origins and cell states associated with tumour location and patient age, and we aimed to further explore the underlying biology of distinct subgroups of DMG using orthogonal data modalities. A retrospective reanalysis identified 242 patient genome-wide DNA methylation array profiles with a methylation classification of DMG_K27. H3 status was known for 168 cases (H3.3 K27M n=130, H3.1 K27M n=20, H3 WT n=18), with EZHIP overexpression or loss of H3K27me3 was confirmed in 13/18 H3 WT cases. Unsupervised clustering identified two distinct methylation subtypes, specific to brainstem (62/64) or thalamic (25/29) location, and highly enriched for gain of chromosome 1q or loss of 5q, respectively. Differential expression analysis from bulk RNA-Seq data recapitulated the recently-published overexpression of ZIC1/4 early development genes in thalamic tumours and an enrichment of HOX-cluster genes in those of brainstem origin. Within DMGs of the thalamus, we further observed a significant overexpression and hypomethylation of NR2E1, a regulator of bivalent promoters via LSD1-H3K4, and essential for stem cell renewal; and CD96, an immune checkpoint blockade target in NK/T-cells. We confirmed differential immune response expression between tumour location by GSEA as well as deconvolution by methylation CIBERSORT from bulk samples, which we were able to characterise further by by single-cell RNA-sequencing. We report unique copy-number and differentially methylated loci as well as differential expression that recapitulates previously reported single-cell metaprogrammes. We also highlight involvement of neural stem cell development programme in thalamus-type tumours as well as evidence of these tumours as being potential targets for immune therapeutic targeting.
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关键词
epigenetic,paediatric-type
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