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Full Text (PDF) Published OnlineFirst January 23, 2019; DOI: 10.1158/0008-5472.CAN-18-1261 Cancer Genome and Epigenome Research Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors Pauline J. Beckmann1, Jon D. Larson1, Alex T. Larsson1, Jason P. Ostergaard1, Sandra Wagner1, Eric P. Rahrmann1,2, Ghaidan A. Shamsan3, George M. Otto1,4, Rory L. Williams1,5, Jun Wang6, Catherine Lee6, Barbara R. Tschida1, Paramita Das1, Adrian M. Dubuc7, Branden S. Moriarity1, Daniel Picard8,9, Xiaochong Wu10, Fausto J. Rodriguez11, Quincy Rosemarie1,12, Ryan D. Krebs1, Amy M. Molan1,13, Addison M. Demer1, Michelle M. Frees1, Anthony E. Rizzardi14, Stephen C. Schmechel14,15, Charles G. Eberhart16, Robert B. Jenkins17, Robert J. Wechsler-Reya6, David J. Odde3, Annie Huang18, Michael D. Taylor10, Aaron L. Sarver1, and David A. Largaespada1 Abstract Medulloblastoma and central nervous system primitive identified several putative proto-oncogenes including Arh- neuroectodermal tumors (CNS-PNET) are aggressive, poorly gap36, Megf10,andFoxr2. Genetic manipulation of these differentiated brain tumors with limited effective therapies. genes demonstrated a robust impact on tumorigenesis Using Sleeping Beauty (SB) transposon mutagenesis, we in vitro and in vivo. We also determined that FOXR2 interacts identified novel genetic drivers of medulloblastoma and with N-MYC, increases C-MYC protein stability, and acti- CNS-PNET. Cross-species gene expression analyses classified vates FAK/SRC signaling. Altogether, our study identified SB-driven tumors into distinct medulloblastoma and several promising therapeutic targets in medulloblastoma CNS-PNET subgroups, indicating they resemble human and CNS-PNET. Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents Significance: A transposon-induced mouse model identi- the first genetically induced mouse model of CNS-PNET and fies several novel genetic drivers and potential therapeutic a rare model of group 3 and 4 medulloblastoma. We targets in medulloblastoma and CNS-PNET. Introduction CNS ganglioneuroblastomas, medulloepitheliomas, and epen- dymoblastomas, although CNS-PNET no longer exists as an Embryonal tumors, including medulloblastoma and central umbrella term (2). Medulloblastoma and CNS-PNET have nervous system primitive neuroectodermal tumors (CNS-PNET), similar histology: densely packed, small cells with hyperchro- represent the most common malignant pediatric brain matic nuclei and little cytoplasm. Medulloblastomas are usu- tumors (1). For ease of historic comparison, CNS-PNET is used ally cerebellar, while CNS-PNETs occur predominantly in the in this article according to the 2007 World Health Organization cerebrum. Aggressive, multimodality treatments improve CNS tumor classification and includes CNS neuroblastomas, survival but produce lifelong side effects, and 5-year survival 1Masonic Cancer Center, Department of Pediatrics, and Center for Genome University of Minnesota, Minneapolis, Minnesota. 14Department of Laboratory Engineering, University of Minnesota, Minneapolis, Minnesota. 2Cancer Research Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota. UK, Cambridge Institute, University of Cambridge, Cambridge, England, United 15Department of Clinical Sciences, College of Medicine, Florida State University, Kingdom. 3Department of Biomedical Engineering, University of Minnesota, Sarasota, Florida. 16Department of Pathology, Ophthalmology and Oncology, Minneapolis, Minnesota. 4Department of Molecular and Cellular Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. University of California, Berkeley, Berkeley, California. 5Department of Bioen- 17Department of Laboratory Medicine and Pathology, Mayo Clinic and Founda- gineering, California Institute of Technology, Pasadena, California. 6Tumor tion, 200 First Street Southwest, Rochester, Minnesota. 18Division of Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Hematology, The Hospital for Sick Children, Toronto, Ontario, Canada. Burnham Prebys Medical Discovery Institute, La Jolla, California. 7Department of Note: Supplementary data for this article are available at Cancer Research Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Online (http://cancerres.aacrjournals.org/). Massachusetts. 8Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, P.J. Beckmann and J.D. Larson are co-first authors of this article. Germany 9Department of Pediatric Oncology, Hematology, and Clinical Immu- nology, Medical Faculty, University Hospital Dusseldorf,€ Dusseldorf,€ Germany. Corresponding Author: David A. Largaespada, University of Minnesota, 129 10Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Cancer Cardiovascular Research Building, 2231 6th Street SE, Minneapolis, MN Center, The Hospital for Sick Children, Toronto, Ontario, Canada. 11Division of 55455. Phone: 612-626-4979; Fax: 612-625-4648; E-mail: [email protected] 12 Neuropathology, Johns Hopkins Hospital, Baltimore, Maryland. McArdle doi: 10.1158/0008-5472.CAN-18-1261 Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin. 13Department of Biochemistry, Molecular Biology, and Biophysics, Ó2019 American Association for Cancer Research. www.aacrjournals.org 905 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst January 23, 2019; DOI: 10.1158/0008-5472.CAN-18-1261 Beckmann et al. rates remain 60%–65% for medulloblastoma and 20%–40% each tumor library were used to generate common insertion sites for CNS-PNET (3). (CIS; P < 0.05). Medulloblastoma and CNS-PNET are molecularly heteroge- fi neous. Medulloblastoma includes four molecular subgroups: Transcriptional pro ling WNT, Sonic hedgehog (SHH), group 3, and group 4; WNT and Isolated tumor RNA (Qiagen, catalog no. 75114) was assessed > SHH are associated with mutations activating those pathways, for quality using capillary electrophoresis (RIN 6.5, Agilent 2100 – but groups 3 and 4 remain less defined (4). A genomic study BioAnalyzer). Paired-end sequencing (30 40 million reads/ by Picard and colleagues identified three distinct CNS-PNET sample) of TruSeq-prepared libraries was performed (Illumina fi subgroups: primitive-neural, oligo-neural, and mesenchy- HiSeq 2000). Raw FASTQ les are available at the NCBI Sequence mal (5). Using methylation- and gene expression–based anal- Read Archive and linked to Gene Expression Omnibus Super- fi yses, Sturm and colleagues identified four molecular sub- Series (GSE122050). FASTQ les were mapped to the MM10 lsl-SB11/þ groups of CNS-PNET associated with gene fusions (6). While genome (T2/Onc and Rosa26 as additional chromosomes; our understanding of the tumor biology has improved, a lack ref. 15) using STAR-Fusion (https://github.com/STAR-Fusion/ of animal models and targetable oncogenic drivers impede STAR-Fusion/wiki). Transcript FPKM values were computed using þ therapeutic development, particularly in group 3/4 medullo- cuffquant and cuffnorm and adjusted by 0.1 (16). blastoma and CNS-PNET. T2/Onc fusion identification We used Sleeping Beauty (SB) transposon mutagenesis to iden- To identify T2/Onc:genome fusions, we analyzed the chimeric. tify novel medulloblastoma and CNS-PNET drivers. Transposi- out.junction and chimeric.out.sam output files from STAR-Fusion tion initiated in neural progenitor cells using Nestin-Cre was used þ to summarize the number of junction (one read contains the alone, with Trp53lsl-R270H/ , or with Pten deficiency to generate T2/Onc:genome junction) and bridge (one paired-end read maps medulloblastomas and CNS-PNETs. These tumors resembled to T2/Onc and the other to the genome) reads present within human medulloblastoma and CNS-PNET histologically and tran- 1,000 bp regions. Fusions supported by 1 junction read or 3 scriptionally. Three candidate oncogenes, Arhgap36, Foxr2, and bridging reads were retained for analysis. Manual detection of Megf10 were validated in vitro and in vivo and their mechanisms T2/Onc(2):Arhgap36 transcripts was done using 500 ng of purified examined. RNA (Invitrogen, catalog no. 15596-018), reverse transcribed (Invitrogen, catalog no. 18080-051) and amplified using primers Materials and Methods in Supplementary Table S1. Generation of transgenic mice Gene cluster similarity Animal studies were conducted using procedures approved Gene cluster similarity was used for unsupervised, unbiased and monitored by the Institutional Animal Care and Use identification of similar gene clusters across transcriptional Committee at the University of Minnesota (UofMN, Minnea- datasets. Transcriptional profile datasets were individually log- polis, MN). Nestin-Cre mice(7)werebredtoeitherT2/Onc transformed, mean-centered, filtered for highly variant genes, and (chromosome 1/15; ref. 8) or T2/Onc2 (chromosome 4; ref. 9) hierarchically clustered using average linkage and (1–Pearson lsl-SB11/þ to generate Nestin-Cre:T2/Onc(2). Rosa26 (10) were correlation) as the distance metric. Gene clusters with node lsl-R270H/þ flox/flox bred to either Trp53 (11) or Pten (12) to generate correlation and size >respective thresholds were retained. lsl-SB11/þ flox/flox lsl-SB11/þ lsl-R270H/þ Rosa26 :Pten or Rosa26 :Trp53 . Cross-dataset cluster pairs were tested for enrichment of common lsl-SB11/þ Nestin-Cre:T2/Onc(2) mice were bred
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