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Series GSE93646 Query DataSets for GSE93646
Status Public on May 29, 2017
Title Microarray-based DNA methylation profiles of primary medulloblastomas
Organism Homo sapiens
Experiment type Methylation profiling by genome tiling array
Summary Identification of novel molecular subgroups
Background:
International consensus recognises four medulloblastoma molecular subgroups - WNT, SHH, Group 3 and Group 4 - each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. Subgroups harbor distinct clinico-pathological and molecular features, underpin current disease sub-classification and initial subgroup-directed therapies are underway in clinical trials (i.e. reduced risk-adapted treatments for favorable-risk WNT patients; SMO inhibitors for SHH patients). However, significant biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved.
Methods:
We undertook comprehensive molecular profiling and unsupervised class discovery (non-negative matrix factorization, t-SNE) of test and validation cohorts to identify consensus primary molecular subgroups within childhood medulloblastoma (<16.0 years), and characterize their clinical and biological significance. Survival modeling was performed in clinically-annotated centrally-reviewed patients (>3.0 years).
Findings:
Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified, characterized by distinct biological/clinical features. For instance, SHH comprised two age-dependent subgroups, while Grp3 and Grp4 each split into two subgroups with significantly different survival rates. Survival analysis identified secondary features predictive of outcome. Cross-validated subgroup-dependent models incorporating these novel subgroups along with secondary features and established disease risk-factors, outperformed current disease risk-stratification schemes. These schema stratified patients into four clinical risk-groups - favorable-risk (91% 5-year survival, 25% of patients), standard-risk (81%, 23%), high-risk (42%, 38%) and very high-risk (28%, 13%) - to be considered for treatment reduction, intensification or novel therapies respectively.
Interpretation:
The discovery of seven novel, clinically-significant, subgroups significantly improves disease risk-stratification and provides a new foundation for future research and clinical investigations.
 
Overall design DNA methylation profiles of 428 medullblastoma were generated from fresh-frozen and formalin-fixed paraffin-embedded materal using the Illumina 450k methylation microarray
 
Contributor(s) Schwalbe EC, Williamson D, Clifford SC
Citation(s) 28545823, 35926460, 38184938
Submission date Jan 16, 2017
Last update date Feb 09, 2024
Contact name Ed Schwalbe
E-mail(s) ed.schwalbe@northumbria.ac.uk
Organization name Northumbria University
Department Applied Sciences
Street address Ellison Place
City Newcastle upon Tyne
ZIP/Postal code NE1 8ST
Country United Kingdom
 
Platforms (1)
GPL13534 Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482)
Samples (428)
GSM2459424 genomic DNA from medulloblastoma_NMB109
GSM2459425 genomic DNA from medulloblastoma_NMB110
GSM2459426 genomic DNA from medulloblastoma_NMB111
Relations
BioProject PRJNA361460

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE93646_RAW.tar 3.6 Gb (http)(custom) TAR (of IDAT)
GSE93646_non_normalized.txt.gz 1012.6 Mb (ftp)(http) TXT
GSE93646_processed_data.txt.gz 1.7 Gb (ftp)(http) TXT
Processed data are available on Series record
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