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| Home > Publications database > Robust molecular subgrouping and reference-free aneuploidy detection in medulloblastoma using low-depth whole genome bisulfite sequencing. |
| Home > Publications database > Robust molecular subgrouping and reference-free aneuploidy detection in medulloblastoma using low-depth whole genome bisulfite sequencing. |
| Journal Article | DKFZ-2025-01275 |
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2025
Biomed Central
London
Abstract: Medulloblastoma 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.
Keyword(s): Humans (MeSH) ; Medulloblastoma: genetics (MeSH) ; Medulloblastoma: classification (MeSH) ; Medulloblastoma: diagnosis (MeSH) ; Cerebellar Neoplasms: genetics (MeSH) ; Cerebellar Neoplasms: classification (MeSH) ; Cerebellar Neoplasms: diagnosis (MeSH) ; Whole Genome Sequencing: methods (MeSH) ; DNA Methylation: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; Aneuploidy (MeSH) ; Child (MeSH) ; Sulfites (MeSH) ; Adolescent (MeSH) ; Child, Preschool (MeSH) ; Aneuploidy ; Classification ; Low-pass ; Medulloblastoma ; Methylation ; Microarray ; Sequencing ; Subgrouping ; WGBS ; Sulfites ; hydrogen sulfite
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