A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Agarwal, 2015 Aryee, 2014, Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays, Bioinformatics, 30, 1363, 10.1093/bioinformatics/btu049 Bentwich, 2005, Identification of hundreds of conserved and nonconserved human microRNAs, Nat. Genet., 37, 766, 10.1038/ng1590 Bortolin-Cavaille, 2009, C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts, Nucleic Acids Res., 37, 3464, 10.1093/nar/gkp205 Buenrostro, 2015, ATAC-seq: a method for assaying chromatin accessibility genome-wide, Curr. Protoc. Mol. Biol., 109, 21 29 21, 10.1002/0471142727.mb2129s109 Cho, 2012, LIN28A is a suppressor of ER-associated translation in embryonic stem cells, Cell, 151, 765, 10.1016/j.cell.2012.10.019 Cook, 2011, RBPDB: a database of RNA-binding specificities, Nucleic Acids Res., 39, D301, 10.1093/nar/gkq1069 Enright, 2003, MicroRNA targets in Drosophila, Genome Biol., 5, R1, 10.1186/gb-2003-5-1-r1 Filippova, 1996, An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes, Mol. Cell. Biol., 16, 2802, 10.1128/MCB.16.6.2802 Gomez, 2015, DNA methylation fingerprint of neuroblastoma reveals new biological and clinical insights, Genom. Data, 5, 360, 10.1016/j.gdata.2015.07.016 Hovestadt, 2013, Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays, Acta Neuropathol, 125, 913, 10.1007/s00401-013-1126-5 Huang, 2008, The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis, Nat. Cell Biol., 10, 202, 10.1038/ncb1681 Johann, 2016, Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes, Cancer Cell, 29, 379, 10.1016/j.ccell.2016.02.001 Johnson, 2007, Adjusting batch effects in microarray expression data using empirical Bayes methods, Biostatistics, 8, 118, 10.1093/biostatistics/kxj037 Jones, 2012, Dissecting the genomic complexity underlying medulloblastoma, Nature, 488, 100, 10.1038/nature11284 Kim, 2012, Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28, Nucleic Acids Res., 40, 3856, 10.1093/nar/gkr1302 Kim, 2013, TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions, Genome Biol, 14, R36, 10.1186/gb-2013-14-4-r36 Kleinman, 2014, Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR, Nat. Genet., 46, 39, 10.1038/ng.2849 Kool, 2014, Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition, Cancer Cell, 25, 393, 10.1016/j.ccr.2014.02.004 Korshunov, 2014, Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity, Acta Neuropathol., 128, 279, 10.1007/s00401-013-1228-0 Lambert, 2013, Differential expression and methylation of brain developmental genes define location-specific subsets of pilocytic astrocytoma, Acta Neuropathol., 126, 291, 10.1007/s00401-013-1124-7 Lee, 2013, Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells, Nucleic Acids Res., 41, 5614, 10.1093/nar/gkt222 Li, 2009, Frequent amplification of a Chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors, Cancer Cell, 16, 533, 10.1016/j.ccr.2009.10.025 Lichner, 2011, The miR-290-295 cluster promotes pluripotency maintenance by regulating cell cycle phase distribution in mouse embryonic stem cells, Differentiation, 81, 11, 10.1016/j.diff.2010.08.002 Lin, 2016, Active medulloblastoma enhancers reveal subgroup-specific cellular origins, Nature, 530, 57, 10.1038/nature16546 Louis, 2016, The 2016 World Health organization classification of tumors of the central nervous system: a summary, Acta Neuropathol., 131, 803, 10.1007/s00401-016-1545-1 Loven, 2013, Selective inhibition of tumor oncogenes by disruption of super-enhancers, Cell, 153, 320, 10.1016/j.cell.2013.03.036 Ma, 2015, A DNMT3A2-HDAC2 complex is essential for genomic imprinting and genome integrity in mouse oocytes, Cell Rep., 13, 1552, 10.1016/j.celrep.2015.10.031 Mack, 2018, Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling, Nature, 553, 101, 10.1038/nature25169 Mack, 2014, Epigenomic alterations define lethal CIMP-positive ependymomas of infancy, Nature, 506, 445, 10.1038/nature13108 Malik, 2014, Genome-wide identification and characterization of functional neuronal activity-dependent enhancers, Nat. Neurosci., 17, 1330, 10.1038/nn.3808 Martin, 2011, Cutadapt removes adapter sequences from high-throughput sequencing reads, EMBnet J., 17, 10, 10.14806/ej.17.1.200 Mehdi, 2018, C3D: a tool to predict 3D genomic interactions between cis-regulatory elements, Bioinformatics, 35, 877, 10.1093/bioinformatics/bty717 Merico, 2010, Enrichment map: a network-based method for gene-set enrichment visualization and interpretation, PLoS One, 5, e13984, 10.1371/journal.pone.0013984 Mermel, 2011, GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers, Genome Biol., 12, R41, 10.1186/gb-2011-12-4-r41 Molenaar, 2012, LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression, Nat. Genet., 44, 1199, 10.1038/ng.2436 Mootha, 2003, PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes, Nat. Genet., 34, 267, 10.1038/ng1180 Murphy, 2013, Silencing of the miR-17∼92 cluster family inhibits medulloblastoma progression, Cancer Res., 73, 7068, 10.1158/0008-5472.CAN-13-0927 Neumann, 2017, A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors, Nat. Med., 23, 1191, 10.1038/nm.4402 Nilsen, 2012, Copynumber: efficient algorithms for single- and multi-track copy number segmentation, BMC Genomics, 13, 591, 10.1186/1471-2164-13-591 Nimura, 2006, Dnmt3a2 targets endogenous Dnmt3L to ES cell chromatin and induces regional DNA methylation, Genes Cells, 11, 1225, 10.1111/j.1365-2443.2006.01012.x Northcott, 2014, Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma, Nature, 511, 428, 10.1038/nature13379 Paraskevopoulou, 2013, DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows, Nucleic Acids Res, 41, W169, 10.1093/nar/gkt393 Peng, 2011, Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells, Stem Cells, 29, 496, 10.1002/stem.591 Pfister, 2009, Novel genomic amplification targeting the microRNA cluster at 19q13.42 in a pediatric embryonal tumor with abundant neuropil and true rosettes, Acta Neuropathol., 117, 457, 10.1007/s00401-008-0467-y Picard, 2012, Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis, Lancet Oncol., 13, 838, 10.1016/S1470-2045(12)70257-7 Powers, 2016, Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma, Nature, 535, 246, 10.1038/nature18632 Rajaram, 2007, DNA sequence of the translocation breakpoints in undifferentiated embryonal sarcoma arising in mesenchymal hamartoma of the liver harboring the t(11;19)(q11;q13.4) translocation, Genes Chromosomes Cancer, 46, 508, 10.1002/gcc.20437 Reimand, 2016, g:Profiler—a web server for functional interpretation of gene lists (2016 update), Nucleic Acids Res., 44, W83, 10.1093/nar/gkw199 Rippe, 2010, The two stem cell microRNA gene clusters C19MC and miR-371-3 are activated by specific chromosomal rearrangements in a subgroup of thyroid adenomas, PLoS One, 5, e9485, 10.1371/journal.pone.0009485 Robinson, 2011, Integrative genomics viewer, Nat. Biotechnol., 29, 24, 10.1038/nbt.1754 Saint-Andre, 2016, Models of human core transcriptional regulatory circuitries, Genome Res., 26, 385, 10.1101/gr.197590.115 Schuijers, 2018, Transcriptional dysregulation of MYC reveals common enhancer-docking mechanism, Cell Rep., 23, 349, 10.1016/j.celrep.2018.03.056 Shannon, 2003, Cytoscape: a software environment for integrated models of biomolecular interaction networks, Genome Res., 13, 2498, 10.1101/gr.1239303 Spence, 2014, A novel C19MC amplified cell line links Lin28/let-7 to mTOR signaling in embryonal tumor with multilayered rosettes, Neuro Oncol., 16, 62, 10.1093/neuonc/not162 Spence, 2014, CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity, Acta Neuropathol., 128, 291, 10.1007/s00401-014-1291-1 Sturm, 2016, New brain tumor entities emerge from molecular classification of CNS-PNETs, Cell, 164, 1060, 10.1016/j.cell.2016.01.015 Sturm, 2012, Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma, Cancer Cell, 22, 425, 10.1016/j.ccr.2012.08.024 Suzuki, 2017, Super-enhancer-mediated RNA processing revealed by integrative MicroRNA network analysis, Cell, 168, 1000, 10.1016/j.cell.2017.02.015 Torchia, 2016, Integrated (epi)-Genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors, Cancer Cell, 30, 891, 10.1016/j.ccell.2016.11.003 Trapnell, 2012, Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks, Nat. Protoc., 7, 562, 10.1038/nprot.2012.016 Triche, 2013, Low-level processing of Illumina Infinium DNA methylation BeadArrays, Nucleic Acids Res., 41, e90, 10.1093/nar/gkt090 Viswanathan, 2009, Lin28 promotes transformation and is associated with advanced human malignancies, Nat. Genet., 41, 843, 10.1038/ng.392 Wang, 2014, Similarity network fusion for aggregating data types on a genomic scale, Nat. Methods, 11, 333, 10.1038/nmeth.2810 Wei, 2013, corrplot: Visualization of a correlation matrix, 230, 11 Whyte, 2013, Master transcription factors and mediator establish super-enhancers at key cell identity genes, Cell, 153, 307, 10.1016/j.cell.2013.03.035 Wilbert, 2012, LIN28 binds messenger RNAs at GGAGA motifs and regulates splicing factor abundance, Mol. Cell, 48, 195, 10.1016/j.molcel.2012.08.004 Yu, 2007, Induced pluripotent stem cell lines derived from human somatic cells, Science, 318, 1917, 10.1126/science.1151526 Zeid, 2018, Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma, Nat. Genet., 50, 515, 10.1038/s41588-018-0044-9 Zhang, 2008, Model-based analysis of ChIP-seq (MACS), Genome Biol., 9, R137, 10.1186/gb-2008-9-9-r137 Zhou, 2010, Silencing of thrombospondin-1 is critical for myc-induced metastatic phenotypes in medulloblastoma, Cancer Res, 70, 8199, 10.1158/0008-5472.CAN-09-4562