Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Methylation profiling data from medulloblastoma tumor samples

ABSTRACT: Smoothened (SMO)-inhibitors recently entered clinical trials for sonic-hedgehog driven medulloblastoma (SHH-MB). Clinical response appears highly variable. To understand the mechanism(s) of primary resistance and to identify pathways co-operating with aberrant SHH-signaling, we sequenced a large cohort of SHH-MBs across all age groups by sequencing, DNA methylation and expression profiling. Our data show that most adults but only half of the pediatric patients with SHH-MB will respond to SMO inhibition as predicted by molecular analysis of the primary tumor and tested in the SHH-xenografts, demonstrating that the next generation of SMO-inhibitor trials should be based on these predictive biomarkers. To further dissect the biological differences between the different age groups within SHH medulloblastomas, we looked at the DNA methylation profiles of SHH medulloblastoma samples. We investigated the DNA methylation profiles of 46 SHH medulloblastomas across all age groups using the Illumina 450k methylation array.

ORGANISM(S): Homo sapiens

SUBMITTER: Marc Remke

PROVIDER: E-GEOD-49377 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.

Kool Marcel M Jones David T W DT Jäger Natalie N Northcott Paul A PA Pugh Trevor J TJ Hovestadt Volker V Piro Rosario M RM Esparza L Adriana LA Markant Shirley L SL Remke Marc M Milde Till T Bourdeaut Franck F Ryzhova Marina M Sturm Dominik D Pfaff Elke E Stark Sebastian S Hutter Sonja S Seker-Cin Huriye H Johann Pascal P Bender Sebastian S Schmidt Christin C Rausch Tobias T Shih David D Reimand Jüri J Sieber Laura L Wittmann Andrea A Linke Linda L Witt Hendrik H Weber Ursula D UD Zapatka Marc M König Rainer R Beroukhim Rameen R Bergthold Guillaume G van Sluis Peter P Volckmann Richard R Koster Jan J Versteeg Rogier R Schmidt Sabine S Wolf Stephan S Lawerenz Chris C Bartholomae Cynthia C CC von Kalle Christof C Unterberg Andreas A Herold-Mende Christel C Hofer Silvia S Kulozik Andreas E AE von Deimling Andreas A Scheurlen Wolfram W Felsberg Jörg J Reifenberger Guido G Hasselblatt Martin M Crawford John R JR Grant Gerald A GA Jabado Nada N Perry Arie A Cowdrey Cynthia C Croul Sydney S Zadeh Gelareh G Korbel Jan O JO Doz Francois F Delattre Olivier O Bader Gary D GD McCabe Martin G MG Collins V Peter VP Kieran Mark W MW Cho Yoon-Jae YJ Pomeroy Scott L SL Witt Olaf O Brors Benedikt B Taylor Michael D MD Schüller Ulrich U Korshunov Andrey A Eils Roland R Wechsler-Reya Robert J RJ Lichter Peter P Pfister Stefan M SM

Cancer cell 20140301 3

Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream ...[more]

PMID: 24651015

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Project description:Background: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. Results: Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T-lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in brain cells. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites, implicating a mechanism involving altered transcription factor binding. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects. Conclusions: These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. Bisulfite converted DNA from 119 samples from Down syndrome patients and controls were hybridised to the Illumina Infinium 450k Human Methylation Beadchip. In addition, we re-analyzed 6 Down syndrome and 6 control cerebellum DNA samples on the 450K BeadChips using an adaptation of the Illumina probe preparation protocol (TrueMethyl kit; Cambridge Epigenetics, CEGX), in which parallel analyses of bisulfite and oxidative bisulfite DNA for each sample allows assessment of the relative contributions of 5mC and 5hmC to net methylation.

Dataset Information

Methylation profiling data from medulloblastoma tumor samples

Publications

Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.

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