Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma (original) (raw)
Accession codes
Data deposits
Short-read sequencing data have been deposited at the European Genome-Phenome Archive (EGA, http://www.ebi.ac.uk/ega/) hosted by the EBI, under accession number EGAS00001000215.
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Acknowledgements
For technical support and expertise we thank: the DKFZ Genomics and Proteomics Core Facility; B. Haase, D. Pavlinic and B. Baying (EMBL Genomics Core Facility); M. Knopf (NCT Heidelberg); the Sanford-Burnham Animal Facility and Cell Imaging, Tissue & Histopathology Shared Resource; and the UCSD Flow Cytometry Core Facility. We also thank Active Motif for the preparation of histone ChIP libraries. This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by the German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Additional support came from the German Cancer Research Center–Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the EMBL International PhD Programme (T.Z.), Dutch Cancer Foundations KWF (2010-4713) and KIKA (M.Ko.), the US National Institutes of Health, National Center for Research Resources (P41 GM103504; G.D.B.), the CancerSys grant MYC-NET (German Federal Ministry of Education and Research, BMBF, 0316076A), the European Commission (Health-F2-2010-260791), and the Helmholtz Alliance PCCC (grant number HA-305). PAN is a Roman Herzog Postdoctoral Fellow funded by the Hertie Foundation and the DKFZ. R.J.W.-R. is the recipient of a Research Leadership Award from the California Institute for Regenerative Medicine (CIRM LA1-01747) and obtained additional support from the National Cancer Institute (5P30CA030199 and R01 CA159859), and the CureSearch for Children's Cancer Foundation.
Author information
Author notes
- Paul A. Northcott, Catherine Lee and Thomas Zichner: These authors contributed equally to this work.
Authors and Affiliations
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany,
Paul A. Northcott, Serap Erkek, Daisuke Kawauchi, Dominik Sturm, David T. W. Jones, Marcel Kool, Andrea Wittmann, Sebastian Stark, Laura Sieber, Huriye Seker-Cin, Linda Linke, Fabian Kratochwil & Stefan M. Pfister - Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0685, USA,
Catherine Lee - Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA,
Catherine Lee, Lourdes Adriana Esparza & Robert J. Wechsler-Reya - European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany,
Thomas Zichner, Adrian M. Stütz, Serap Erkek, Benjamin Raeder & Jan O. Korbel - The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada,
David J. H. Shih, Marc Remke, Florence M. G. Cavalli & Michael D. Taylor - Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany,
Volker Hovestadt, Marc Zapatka, Wei Wang, Ursula D. Weber & Peter Lichter - The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada,
Scott Zuyderduyn & Gary D. Bader - Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA,
Scott VandenBerg - Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia,
Marina Ryzhova - Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany,
Natalie Jäger, Ivo Buchhalter, Benedikt Brors & Roland Eils - Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany,
Charles D. Imbusch, Gideon Zipprich, Chris Lawerenz & Jürgen Eils - Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany,
Sabine Schmidt, Nicolle Diessl, Stephan Wolf & Stefan Wiemann - Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany,
Hans-Jörg Warnatz, Thomas Risch & Marie-Laure Yaspo - Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany,
Cynthia C. Bartholomae & Christof von Kalle - Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany,
Christof von Kalle, Roland Eils & Peter Lichter - 1st Department of Pathology and Experimental Cancer Research, Semmelweis University SE, II.sz. Gyermekklinika, Budapest 1094, Hungary,
Eszter Turányi - 2nd Department of Pediatrics, Semmelweis University, SE, II.sz. Gyermekklinika, Budapest 1094, Hungary,
Peter Hauser - Division of Neurosurgery, Glioma Immunotherapy Group, Lund University, Paradisgatan 2, Lund 221 00, Sweden,
Emma Sanden, Anna Darabi & Peter Siesjö - Department of Clinical Sciences, Lund University, Paradisgatan 2, Lund 221 00, Sweden,
Emma Sanden, Anna Darabi & Peter Siesjö - Department of Pediatric Oncology, Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic,
Jaroslav Sterba & Karel Zitterbart - Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, Prague 150 06, Czech Republic,
David Sumerauer - Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands,
Peter van Sluis, Rogier Versteeg, Richard Volckmann & Jan Koster - Department of Neurosurgery, Tübingen University Hospital, Hoppe-Seyler Strasse 3, Tübingen 72076, Germany,
Martin U. Schuhmann & Martin Ebinger - Division of Immunobiology, Program in Cancer Pathology of the Divisions of Experimental Hematology and Pathology, Program in Hematologic Malignancies of the Cancer and Blood Disease Insitute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 452229, USA,
H. Leighton Grimes - Department of Developmental Neurobiology, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA,
Giles W. Robinson & Richard J. Gilbertson - Department of Oncology, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA,
Giles W. Robinson, Amar Gajjar & Richard J. Gilbertson - Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany,
Martin Mynarek, Katja von Hoff & Stefan Rutkowski - Department of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, Bonn 53105, Germany,
Torsten Pietsch - Cnopf'sche Kinderklinik, Nürnberg Children’s Hospital, St-Johannis-Mühlgasse 19, Nürnberg 90419, Germany,
Wolfram Scheurlen - Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany,
Jörg Felsberg & Guido Reifenberger - Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany,
Andreas E. Kulozik, Olaf Witt & Stefan M. Pfister - Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany,
Andreas von Deimling & Andrey Korshunov - Division of Neurosurgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada,
Michael D. Taylor - EMBL, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SD, UK,
Jan O. Korbel
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Contributions
P.A.N., C.L., T.Z., A.M.S., D.K., L.A.E., W.W., A.W., S.St., L.S., H.S.-C., L.L., F.K., J.F., B.R., S.Sc., N.D., S.Wo., T.R., C.C.B., P.v.S. and A.K. performed and/or coordinated experimental or technical work. P.A.N., T.Z., S.E., D.J.H.S., V.H., M.Z., S.Z., G.D.B., N.J., I.B., C.D.I., G.Z., J.E., R.Vo., J.K. and J.O.K. performed and/or coordinated data analysis. M.Re., F.M.G.C., S.V., M.Ry., E.T., P.H., E.S., A.D., P.S., J.S., K.Z., D.Su., M.U.S., M.E., H.L.G., G.W.R., A.G., M.M., K.v.H., S.R., T.P., W.S., R.J.G., A.K. and M.D.T. contributed data, provided reagents, or patient materials. P.A.N., C.L., T.Z., S.E., D.J.H.S., V.H., D.St., D.T.W.J., M.K., S.Z., H.-J.W., R.J.G., M.D.T., P.Li., J.O.K., R.J.W.-R. and S.M.P. prepared the initial manuscript and display items. P.A.N., G.D.B., S.Wi., B.B., C.L., M-L.Y., U.D.W., C.v.K., R.V., G.R., A.E.K., A.v.D., O.W., R.E., P.Li., J.O.K., R.J.W.-R. and S.M.P. provided project leadership. P.A.N., J.O.K., R.J.W.-R. and S.M.P. co-conceived and led the study. P.Li., J.O.K., R.J.W.-R. and S.M.P are co-senior authors of this study.
Corresponding authors
Correspondence toPeter Lichter, Jan O. Korbel, Robert J. Wechsler-Reya or Stefan M. Pfister.
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Competing interests
The authors declare no competing financial interests.
Extended data figures and tables
Extended Data Figure 1 Recurrent somatic copy-number aberrations target a common region on 9q34.
Affymetrix SNP6 copy-number output for 22 primary medulloblastomas from the published8 MAGIC series exhibiting focal somatic copy-number aberrations within the 9q34 region of interest defined by WGS in the current study. Of the affected samples, medulloblastoma subgroup information was available for 15 of 22 cases: SHH (n = 1*), group 3 (n = 11) and group 4 (n = 3). Close examination of the single non-group 3/group 4 medulloblastoma affected by a focal copy-number event in the region (MAGIC_MB1318, SHH) revealed that this sample exhibits a homozygous deletion (in the context of broad chr9q deletion) specifically overlapping TSC1 and is therefore unlikely to be related to the events which target GFI1B for transcriptional activation. Indicated coordinates are based on the hg18 reference genome (NCBI Build 36.1) that was used in the original MAGIC study.
Extended Data Figure 2 Non-functional DDX31–GFI1B fusion transcripts detected by RNA-seq.
a, A complex SV on 9q34 in ICGC_MB9 resulted in expression of DDX31 (exon 19) fused to GFI1B (intron 2, antisense orientation). Note the intronic reads in GFI1B after the fusion breakpoint. b, 9q34 inversions in ICGC_MB247 resulted in expression of DDX31 (exon 19) fused to GFI1B (exon 2, sense orientation). This fusion transcript included a frameshift, inferred to generate a C-terminal-truncated DDX31 protein and no GFI1B protein from this fused allele.
Extended Data Figure 3 Expression and correlation of 9q34 genes in medulloblastoma subgroups.
a–c, Box-plots summarizing expression of BARHL1 (a), DDX31 (b) and GTF3C4 (c) according to medulloblastoma subgroup. Data set includes 375 medulloblastomas profiled on the Affymetrix U133plus2 array. d, Pearson correlation analysis showing correlated expression of DDX31 with BARHL1 and GTF3C4 in group 3 and group 4 medulloblastomas. DDX31 expression is positively correlated with both BARHL1 (r = 0.741) and GTF3C4 (r = 0.622). e, PRRC2B expression in medulloblastoma subgroups. Samples are from the same series summarized in a–c. f, Distribution of H3K27ac ChIP-seq signal at predicted enhancers in group 3 medulloblastomas (data for MAGIC_MB360 are shown). Enhancer regions are plotted in increasing order based on their input-normalized H3K27ac signal. Super-enhancers are defined as the population of enhancers above the inflection point of the curve (horizontal dashed grey line). Positions of the predicted BARHL1/DDX31 and PRRC2B super-enhancers described in the text are highlighted.
Extended Data Figure 4 Frequency and distribution of GFI1/GFI1B activation in medulloblastoma subgroups.
a, Stacked bar graph indicates the proportion of _GFI1/GFI1B_-expressing cases in each of the four medulloblastoma subgroups, as determined by Affymetrix gene expression profiling of two independent cohorts (n = 727). b, Stacked bar graph indicates the proportion of GFI1/GFI1B-positive cases in each of the four medulloblastoma subgroups, as determined by immunohistochemistry performed with anti-GFI1 and anti-GFI1B antibodies on formalin-fixed paraffin-embedded sections derived from a medulloblastoma clinical trial cohort (HIT2000, NCT00303810; n = 156). c–f, Representative positive and negative immunohistochemistry results for group 3 medulloblastomas stained with anti-GFI1 (c, d) and anti-GFI1B (e, f) antibodies, respectively.
Extended Data Figure 5 Demographic and clinical characteristics of GFI1/GFI1B-activated group 3 medulloblastoma.
a, b, Unsupervised hierarchical clustering of group 3 medulloblastoma samples profiled by Affymetrix gene expression array (a) or Illumina 450K DNA methylation array (b). c, Patient characteristics, including age, gender, histological subtype (histology) and metastatic status (M-stage) for group 3 medulloblastomas stratified according to GFI1 and GFI1B expression status. Both gene expression and immunohistochemistry cohorts are summarized. d, e, Overall survival of group 3 medulloblastomas stratified by GFI1 and GFI1B expression status for both our gene expression (d) and immunohistochemistry series (e).
Extended Data Figure 6 Summary of GFI1 SVs detected by WGS in group 3 medulloblastoma.
a, Schematics depicting the six different GFI1 translocations detected by large-insert paired-end sequencing of our _GFI1_-activated validation series. b, WGS coverage plots showing SVs affecting the GFI1 locus in _GFI1_-activated medulloblastomas sequenced in our series. c, Fluorescence in situ hybridization (FISH) analysis of MAGIC_MB1338 validating the unbalanced t(1:9) translocation (shown in a) predicted by WGS.
Extended Data Figure 7 Chromatin states proximal to SVs observed in _GFI1_-activated group 3 medulloblastomas.
a–d, ChIP-seq (H3K27ac and H3K9ac) and WGBS data respectively highlighting the active chromatin and methylation states present in the regions proximal to SV breakpoints identified in GFI1 translocation cases. e, Schematic summarizing the series of focal tandem duplications observed approximately ∼45 kb downstream of GFI1 in group 3 medulloblastomas (n = 3; ICGC_MB18 is shown as a representative case). Activating and repressive histone marks overlapping the region of interest are shown for a non-_GFI1_-activated group 3 medulloblastoma (MAGIC_MB360) and the tandem duplication case (ICGC_MB18).
Extended Data Figure 8 Association between GFI1/GFI1B activation and MYC in group 3 medulloblastoma.
a, MYC expression in group 3 medulloblastomas (n = 168) according to GFI1 and GFI1B activation status. b, Gene sets with significant enrichment in _GFI1/GFI1B_-associated genes from the MSigDB c2 gene set collection. The collection highlighted in red is the only result found that shows a significant enrichment in both GFI1 and GFI1B associated genes and a clear connection to a known pathway. c, Heat-map of the expression values for the 50 genes in the KIM_MYC_AMPLIFICATION_TARGETS_UP gene set with the most significant association with GFI1 or GFI1B expression (the complete gene set contains 187 profiled genes). Genes are ordered top to bottom from most to least significant. A set of 90 group 3 medulloblastomas included in the analysis is displayed. Sample-wise hierarchical clustering was performed only to enhance the visual organization of the heat map. d, Affymetrix SNP6 copy-number output for 82 primary group 3 medulloblastomas from the published MAGIC series, highlighting the incidence of MYC amplification in the context of _GFI1/GFI1B_-activation. MYC amplification was found at a comparable frequency in both _GFI1_-activated (n = 2 of 14, 14.3%) and non-_GFI1/GFI1B_-activated (n = 10 of 57, 17.5%) group 3 medulloblastomas. Indicated coordinates are based on the hg18 (NCBI Build 36.1) reference genome that was used in the original MAGIC study.
Extended Data Figure 9 Phenotypic characteristics of novel GFI1/GFI1B orthotopic mouse models.
a, b, Bioluminescent imaging of animals injected with either _GFI1_- (a) or _GFI1B_-expressing (b) neural stem cells at the indicated time points. No tumour signal was detectable in these animals. c, Haematoxylin and eosin staining of cerebellar sections derived from MYC + GFI1B tumour-bearing mice. d, Immunofluorescence imaging of cerebellar sections from MYC + GFI1B tumours stained with the indicated antibodies.
Supplementary information
Supplementary Table 1
This file contains the details on the sequencing cohorts included in the main paper. (XLSX 19 kb)
Supplementary Table 2
RNA-seq analysis did not disclose evidence for possible GFI1 fusion genes (data not shown), suggesting that the detected rearrangements contribute to GFI1 activation by alternative mechanisms. This table shows that observed translocation partners showed no apparent preference for intragenic or intergenic breakpoints. (XLSX 15 kb)
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Northcott, P., Lee, C., Zichner, T. et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.Nature 511, 428–434 (2014). https://doi.org/10.1038/nature13379
- Received: 12 January 2014
- Accepted: 15 April 2014
- Published: 22 June 2014
- Issue Date: 24 July 2014
- DOI: https://doi.org/10.1038/nature13379