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Gain-Of-Function Genetic Alterations of G9a Drive Oncogenesis

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Published OnlineFirst April 8, 2020; DOI: 10.1158/2159-8290.CD-19-0532 RESEARCH ARTICLE Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis Shinichiro Kato 1 , Qing Yu Weng 1 , Megan L. Insco 2 , 3 , 4 , Kevin Y. Chen 2 , 3 , 4 , Sathya Muralidhar 5 , Joanna Pozniak 5 , Joey Mark S. Diaz5 , Yotam Drier 6 , 7 , 8 , Nhu Nguyen 1 , Jennifer A. Lo 1 , Ellen van Rooijen 2 , 3 , Lajos V. Kemeny 1 , Yao Zhan1 , Yang Feng 1 , Whitney Silkworth 1 , C. Thomas Powell 1 , Brian B. Liau 9 , Yan Xiong 10 , Jian Jin 10 , Julia Newton-Bishop5 , Leonard I. Zon 2 , 3 , Bradley E. Bernstein 6 , 7 , 8 , and David E. Fisher 1 . Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst April 8, 2020; DOI: 10.1158/2159-8290.CD-19-0532 ABSTRACT Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β -catenin pathway in melanoma. This study identifi es previ- ously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identifi ed as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplifi ed G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations. SIGNIFICANCE: Oncogenic G9a abnormalities drive tumorigenesis and the “cold” immune microenvi- ronment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore “hot” tumor immune microenvi- ronments. INTRODUCTION and NSD2 ( 8 ) are also targeted by gain-of-function genetic alterations that engender oncogenic properties. The identifi cation and targeting of genomically altered Another histone methyl transferase, G9a (gene name Euchro- oncogenic drivers remains a compelling therapeutic strategy matic Histone lysine MethylTransferase 2, EHMT2 ), encodes a for otherwise incurable cancers. Disruption of the epigenetic primary SET domain–containing enzyme that can catalyze landscape is a relatively common event in cancer, often due monomethylation and dimethylation of histone H3K9 in a to genetic alterations of epigenetic regulatory genes ( 1 ). One heterodimeric complex with G9a-like protein (GLP; ref. 9 ). G9a epigenetic modifi er that undergoes somatic recurrent acti- plays critical roles in multiple developmental processes and cell vating oncogenic mutations is enhancer of zeste homolog 2 fate decisions through modulation of H3K9me2 levels ( 10 ). (EZH2), which can silence expression of target genes (includ- Genome-wide analysis suggests that H3K9me2 is functionally ing tumor suppressors) through H3K27 trimethylation ( 2 ). linked with transcriptional repression ( 11 ). Multiple studies Recurrent mutations of EZH2 have been observed within its have reported elevated G9a expression in various cancers and SET domain, which is well conserved across SET domain– suggested functional linkages with malignant behaviors of containing histone methyltransferases (HMT) and is essential cancer cells (e.g., aberrant proliferation, chemoresistance, and for their enzymatic activity ( 3–5 ). The SET domain–containing metastasis) by silencing tumor suppressors ( 12 ) and/or activat- HMTs Mixed Lineage Leukemia 1 (MLL1; ref. 6 ), MLL3 ( 7 ), ing survival genes ( 13 ) or epithelial-to-mesenchymal transition (EMT) programs ( 14 ). In addition, recent functional studies have implicated G9a’s oncogenic role in MYC-driven tumori- 1 Cutaneous Biology Research Center, Department of Dermatology, Mas- genesis ( 15 ). However, genomic alterations of G9a that could sachusetts General Hospital, Harvard Medical School, Charlestown, Mas- directly trigger oncogenesis have not been previously identi- sachusetts. 2 Howard Hughes Medical Institute, Chevy Chase, Maryland. 3 Stem Cell Program and Division of Pediatric Hematology/Oncology, Bos- fi ed. Here we report the occurrence of recurrent activating ton Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical mutations within the SET domain of G9a and demonstrate School, Boston, Massachusetts. 4 Department of Stem Cell and Regen- their oncogenic function. We further fi nd that genomic copy erative Biology, Harvard Stem Cell Institute, Cambridge, Massachusetts. gains of G9a are relatively common in melanomas and other 5 Institute of Medical Research at St James’s, University of Leeds, Leeds, United Kingdom. 6 Center for Cancer Research, Massachusetts General malignancies, and they display very similar oncogenic activity Hospital, Boston, Massachusetts. 7 Department of Pathology, Massachu- in vitro and in vivo . G9a is found to function through repression setts General Hospital, Harvard Medical School, Boston, Massachusetts. of DKK1, a negative regulator of the WNT pathway, an impor- 8 Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 9 Depart- tant developmental pathway heavily implicated in numerous ment of Chemistry and Chemical Biology, Harvard University, Cambridge, malignancies including some in which its overactivity has Massachusetts. 10 Mount Sinai Center for Therapeutics Discovery, Depart- ment of Pharmaceutical Sciences and Oncological Sciences, Tisch Cancer lacked prior mechanistic explanation. Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Note: Supplementary data for this article are available at Cancer Discovery RESULTS Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Author: David E. Fisher, Massachusetts General Hospital , G9a Is Recurrently Mutated and Amplifi ed in Bartlett 655, Fruit Street, Boston, MA 02114 . Phone: 617-643-5428; Patients with Melanoma E-mail: dfi [email protected]. edu We interrogated publicly available whole-exome sequencing Cancer Discov 2020;10:980–97 data for human melanomas and identifi ed 6 cases harboring doi: 10.1158/2159-8290.CD-19-0532 recurrent G9a point mutations at glycine 1069 ( Fig. 1A ): four ©2020 American Association for Cancer Research. cases with G1069L and two cases with G1069W (P = 8.45e-13). JULY 2020 CANCER DISCOVERY | 981 Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst April 8, 2020; DOI: 10.1158/2159-8290.CD-19-0532 RESEARCH ARTICLE Kato et al. 0.08 0.1 0.2 1p12 NOTECH2 AC1q21.3 SETDB1 TAD: transcription activation domain G1069L (4 cases) 1 1q31.2 Poly Glu: poly glutamine-rich domain G1069W (2 cases) 1q32.1 1q44 NLS: nuclear localization signal P = 8.45e-13 SMYD3 2 3p13 MITF SET: methyltransferase catalytic domain 4q12 KIT 5p15.33 T555I S895F P1134L 3 TERT 5p15.31 5p15.2 Poly N N Ankyrin Pre- Post- 4 5p15.2 TAD L L SET Glu S S repeat SET SET 5p13.2 NEDD9 6p24.3 1 280 300 326 341 348 357 362 684 882 925 1038 1160 1180 1210 5 6p21.33 G9a 6 6q12 Recurrent nonsynonymous mutation 7q22.3 7 7q34 BRAF Nonsynonymous mutation 7q36.1 EZH2 8 8q11.22 G9a G1069 8q21.13 PDL1 EZH2 Y641 9 8q24.3 B Chromosomes 10 11q13.3 JAK2 G9a VRLQLYRTAK–MGWGVRALQTIPQGTFICEYVGELISDAEADVR––––EDD–SYLFDLDNKDGE 11q14.1 CCND1 11 11q22.1 GLP ARLQLYRTRD–MGWGVRSLQDIPPGTFVCEYVGELISDSEADVR–––––EED–SYLFDLDNKDGE 12 12q14.1 CDK4 SETDB1 VRLQLFKTQN–KGWGIRCLDDIAKGSFVCIYAGKILTDDFADKEGLEMGDE––––YFANLDHIESV 12q15 MDM2 SUV39H1 YDLCIFRTDDGRGWGVRTLEKIRKNSFVMEYVGEIITSEEAERRGQIYDRQGA–TYLFDLDYVE–D 13 12q15 14 15q24.3 SUV39H2 YSLCIFRTSNGRGWGVKTLVKIKRMSFVMEYVGEVITSEEAERRGQFYDNKGI–TYLFDLDYES–D 15 15q26.2 EZH1 –KHLLLAPSDVAGWGTFIKESVQKNEFISEYCGELISQDEADRRGKVYD–KYMSSFLFNLN––––N 16 17q23.2 17 17q25.3 EZH2 –KHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYD–KYMCSFLFNLN–––N 18 19p13.2 19 MLL –––VGVYRSPIHGRGLFCKRNIDAGEMVIEYAGNVIRSIQTDKREKYYDSKGIGCYMFRID–––D 20 20q13.2 21 22q13.1 MLL2 –––VGVYRSAIHGRGLFCKRNIDAGEMVIEYSGIVIRSVLTDKREKFYDGKGIGCYMFRMD–––D 0.25 10 10 10 10 10 22 22q13.2 EP300 Conserved AA: − − − − − L3MBTL2 ** ** 2 3 6 10 20 AdoMet Catalytic Significance of amplification acceptor site (q-value, FDR) Figure 1. G9a recurrent mutations G1069L/W enhance catalytic activity and melanomagenesis. A, Domain architecture of human G9a and mutations reported in 16 publicly available whole-exome sequencing datasets of patient-derived melanomas (2,034 cases). Red arrowheads indicate recurrent non- synonymous mutations. B, Alignment of a portion of the human G9a SET domain with 8 different SET domain–containing histone methyltransferases. The blue and red columns indicate the highly conserved catalytic site tyrosine (e.g., EZH2 Y641 or G9a Y1067) and glycine (e.g., G9a G1069 or EZH2 G643), respectively. C, Genomic Identification of Significant Targets in Cancer analysis (see Methods) revealed significant regions of recurrent focal chromo- somal copy-number gain/amplification among TCGA human melanomas. continued( on following page) The recurrently mutated site glycine 1069 resides within the lytic activity on several substrates, but neither G9a G1069L nor highly conserved SET methyltransferase domain (Fig. 1A and G9a G1069W displayed significant activity in the absence of GLP B; Supplementary Fig. S1A and S1B; Supplementary Table S1) (Fig.
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  • De Novo Deletion of Chromosome 11Q12.3 in Monozygotic Twins

    De Novo Deletion of Chromosome 11Q12.3 in Monozygotic Twins

    CASE REPORT Open Access De novo deletion of chromosome 11q12.3 in monozygotic twins affected by Poland Syndrome Carlotta Maria Vaccari1†, Maria Victoria Romanini2†, Ilaria Musante1, Elisa Tassano3, Stefania Gimelli4, Maria Teresa Divizia3, Michele Torre5, Carmen Gloria Morovic6, Margherita Lerone3, Roberto Ravazzolo1,3,7 and Aldamaria Puliti1,3,7* Abstract Background: Poland Syndrome (PS) is a rare disorder characterized by hypoplasia/aplasia of the pectoralis major muscle, variably associated with thoracic and upper limb anomalies. Familial recurrence has been reported indicating that PS could have a genetic basis, though the genetic mechanisms underlying PS development are still unknown. Case presentation: Here we describe a couple of monozygotic (MZ) twin girls, both presenting with Poland Syndrome. They carry a de novo heterozygous 126 Kbp deletion at chromosome 11q12.3 involving 5 genes, four of which, namely HRASLS5, RARRES3, HRASLS2, and PLA2G16, encode proteins that regulate cellular growth, differentiation, and apoptosis, mainly through Ras-mediated signaling pathways. Conclusions: Phenotype concordance between the monozygotic twin probands provides evidence supporting the genetic control of PS. As genes controlling cell growth and differentiation may be related to morphological defects originating during development, we postulate that the observed chromosome deletion could be causative of the phenotype observed in the twin girls and the deleted genes could play a role in PS development. Keywords: Chromosome 11q deletion, Congenital abnormalities, Monozygotic twins, Poland syndrome, CNV, HRASLS5, HRASLS2, RARRES3, PLA2G16 Background Poland Syndrome (PS) (OMIM 173800) is characterized Vaccari et al. BMC Medical Genetics 2014, 15:63 Page 2 of 7 http://www.biomedcentral.com/1471-2350/15/63 proximal and distal muscles, and sternum, develop accor- indication for surgical intervention.