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000302157 1001_ $$aThompson, Dean$$b0
000302157 245__ $$aRobust molecular subgrouping and reference-free aneuploidy detection in medulloblastoma using low-depth whole genome bisulfite sequencing.
000302157 260__ $$aLondon$$bBiomed Central$$c2025
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000302157 520__ $$aMedulloblastoma comprises four principal molecular disease groups and their component subgroups, each with distinct molecular and clinical features. Group assignment is currently achieved diagnostically using Illumina DNA methylation microarray. Whole-genome sequencing (WGS) capacity is rapidly expanding in the clinical setting and the development of platform-independent, sequence-based assays of molecular group offers significant potential. Specifically, whole-genome bisulfite sequencing (WGBS) enables assessment of genome-wide methylation status at single-base resolution, however its routine application has been limited by high DNA input requirements, cost, and a lack of pipelines tailored to more rapidly-acquired and cost-effective low-depth (< 10x) sequencing data. We utilised WGBS data for 69 medulloblastomas, comprising 35 in-house low-depth (~ 10x) and 34 publicly available high-depth (~ 30x) samples, alongside cerebellar controls (n = 8), all with matched DNA methylation microarray data. We assessed quality (QC) and imputation approaches using low-pass WGBS data, assessed inter-platform correlation and identified molecular groups and subgroups by directly integrating matched/associated loci from WGBS sample data with the MNP classifier probeset. We further assessed and optimised reference-free aneuploidy detection using low-pass WGBS and assessed concordance with microarray-derived calls. We developed and optimised pipelines for processing, QC, and analysis of low-pass WGBS data, suitable for routine molecular subgrouping and reference-free aneuploidy assessment. We demonstrate that low-pass WGBS data can (i) be integrated into existing array-trained models with high assignment probabilities for both principal molecular groups (97% concordance) and molecular subgroups (94.2% concordance), and (ii) detect clinically relevant focal copy number changes, including SNCAIP, with greater sensitivity than microarray approaches. Low-pass WGBS performs equivalently to array-based methods at comparable cost. Finally, its ascertainment of the full methylome enables elucidation of additional biological complexity and inter-tumoural heterogeneity that has hitherto been inaccessible. These findings provide proof-of-concept for clinical adoption of low-pass WGBS, applied using standard WGS technology.
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000302157 650_7 $$2Other$$aAneuploidy
000302157 650_7 $$2Other$$aClassification
000302157 650_7 $$2Other$$aLow-pass
000302157 650_7 $$2Other$$aMedulloblastoma
000302157 650_7 $$2Other$$aMethylation
000302157 650_7 $$2Other$$aMicroarray
000302157 650_7 $$2Other$$aSequencing
000302157 650_7 $$2Other$$aSubgrouping
000302157 650_7 $$2Other$$aWGBS
000302157 650_7 $$2NLM Chemicals$$aSulfites
000302157 650_7 $$0OJ9787WBLU$$2NLM Chemicals$$ahydrogen sulfite
000302157 650_2 $$2MeSH$$aHumans
000302157 650_2 $$2MeSH$$aMedulloblastoma: genetics
000302157 650_2 $$2MeSH$$aMedulloblastoma: classification
000302157 650_2 $$2MeSH$$aMedulloblastoma: diagnosis
000302157 650_2 $$2MeSH$$aCerebellar Neoplasms: genetics
000302157 650_2 $$2MeSH$$aCerebellar Neoplasms: classification
000302157 650_2 $$2MeSH$$aCerebellar Neoplasms: diagnosis
000302157 650_2 $$2MeSH$$aWhole Genome Sequencing: methods
000302157 650_2 $$2MeSH$$aDNA Methylation: genetics
000302157 650_2 $$2MeSH$$aMale
000302157 650_2 $$2MeSH$$aFemale
000302157 650_2 $$2MeSH$$aAneuploidy
000302157 650_2 $$2MeSH$$aChild
000302157 650_2 $$2MeSH$$aSulfites
000302157 650_2 $$2MeSH$$aAdolescent
000302157 650_2 $$2MeSH$$aChild, Preschool
000302157 7001_ $$aCastle, Jemma$$b1
000302157 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b2$$udkfz
000302157 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b3$$udkfz
000302157 7001_ $$aBailey, Simon$$b4
000302157 7001_ $$aHicks, Debbie$$b5
000302157 7001_ $$aClifford, Steven C$$b6
000302157 7001_ $$aSchwalbe, Edward C$$b7
000302157 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-025-02049-1$$gVol. 13, no. 1, p. 132$$n1$$p132$$tActa Neuropathologica Communications$$v13$$x2051-5960$$y2025
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