Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Methylation 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 83 SHH medulloblastomas across all age groups using the Illumina 450k methylation array.

ORGANISM(S): Homo sapiens

SUBMITTER: Marcel Kool

PROVIDER: E-GEOD-49576 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

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

Similar Datasets

Project description:Medulloblastomas (MBs) are cerebellar tumors that can be classified into molecularly distinct subgroups that differ in pathology and prognosis. The mechanisms that underlie subgroup specification are largely unknown. While human SHH MBs express MYCN, Group3 (G3) MBs are associated with c-MYC (MYC) overexpression and often show metastasis that confers a poor prognosis. Although MYC proteins are thought to be functionally exchangeable, ectopic expression of Myc or N-myc in Trp53-/-;Cdkn2c-/- cerebellar granule neuron progenitors (GNPs) induces G3 and SHH MBs, respectively, demonstrating that each Myc protein has distinct biological properties. We now show that Myc and N-myc differ in their affinity to Miz1 and that Myc, but not N-myc, effectively recruits Miz1 to its target sites on chromatin. The interaction of Myc with Miz1 is required for the genesis of G3 MB. Myc suppresses ciliogenesis and âreprogramsâ the transcriptome of SHH-dependent GNPs to stem-like cells by repressing genes highly expressed in SHH MB via Miz1. Consistently, target genes of Myc/Miz1 are repressed in human G3 MBs but not in other MB subgroups. Collectively, the data show that the interaction of Myc with Miz1 is a defining hallmark of G3 MB development. In this study, we show that Myc and N-myc differ in their affinity for Miz1, and Myc/Miz1 interaction is required for Group3 medulloblastoma (MB). The gene expression profiles of these tumors were compared to our previously published Group3 MB model as well as SHH model of MB (Kawachi et al., 2012, Cancer Cell). Cerebellar granule neuron progenitors (GNPs) [dka220-222] from postnatal (P) 6 Math1-GFP;Trp53-/-;Cdkn2c-/-. For SHH medulloblastomas, [dka204-206] and [blm015-017 or dka050-dka051], spontaneous medulloblastomas from Cdkn2c-/-;Trp53Fl/Fl;Nestin-Cre (Kawachi et al., 2012, Cancer Cell) and Ptch1+/-;Cdkn2c-/- (Uziel et al., 2005, Genes Dev) were used, respectively. Myc- [dka201-203] and MycV394D (termed MycVD thereafter)- [bvo017-bvo023] tumors were from Trp53-/-;Cdkn2c-/- cerebella of P6-P7 pups. Myc/ÎPOZ tumors [bvo002-bvo006] were obtained from Trp5Fl/Fl;Miz1ÎPOZ/POZ;Nestin-Cre cerebella of P6-P7 pups.

Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumorâ??s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma. ChIP-Seq experiments for Miz1, c-Myc and NMyc from murine medulloblastoma material. Either sorted tumor cells (Miz1 and c-Myc) or spheres from tumor cells (Miz1 and NMyc) were used. Input-samples were sequenced as controls. RNA-Seq from G3 medulloblastomas after restoration of Atoh1 expression.

Dataset Information

Methylation data from medulloblastoma tumor samples

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets