دورية أكاديمية
أعرض في EDS

Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.

التفاصيل البيبلوغرافية
العنوان: Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.
المؤلفون: Grünewald TG; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France., Bernard V; Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France., Gilardi-Hebenstreit P; École Normale Supérieure (ENS), Institut de Biologie de l'ENS (IBENS), INSERM U1024, CNRS UMR8197, Paris, France., Raynal V; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France.; Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France., Surdez D; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France., Aynaud MM; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France., Mirabeau O; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France., Cidre-Aranaz F; Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain., Tirode F; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France., Zaidi S; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France., Perot G; INSERM U916 Biology of Sarcomas, Institut Bergonié, Bordeaux, France., Jonker AH; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France., Lucchesi C; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France., Le Deley MC; Département d'Epidémiologie et de Biostatistiques, Institut Gustave Roussy, Villejuif, France., Oberlin O; Département de Pédiatrie, Institut Gustave Roussy, Villejuif, France., Marec-Bérard P; Institute for Pediatric Hematology and Oncology, Leon-Bérard Cancer Center, University of Lyon, Lyon, France., Véron AS; INSERM U1052, Léon-Bérard Cancer Centre, Cancer Research Center of Lyon, Lyon, France., Reynaud S; Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France., Lapouble E; Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France., Boeva V; INSERM U900, Bioinformatics, Biostatistics, Epidemiology and Computational Systems Biology of Cancer, Institut Curie Research Center, Paris, France.; Mines ParisTech, Fontainebleau, France., Rio Frio T; Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France., Alonso J; Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain., Bhatia S; Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama, Birmingham, Alabama, USA., Pierron G; Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France., Cancel-Tassin G; Centre de Recherche sur les Pathologies Prostatiques (CeRePP)-Laboratory for Urology, Research Team 2, UPMC, Hôpital Tenon, Paris, France., Cussenot O; Centre de Recherche sur les Pathologies Prostatiques (CeRePP)-Laboratory for Urology, Research Team 2, UPMC, Hôpital Tenon, Paris, France., Cox DG; INSERM U1052, Léon-Bérard Cancer Centre, Cancer Research Center of Lyon, Lyon, France., Morton LM; Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Bethesda, Maryland, USA., Machiela MJ; Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Bethesda, Maryland, USA., Chanock SJ; Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Bethesda, Maryland, USA., Charnay P; École Normale Supérieure (ENS), Institut de Biologie de l'ENS (IBENS), INSERM U1024, CNRS UMR8197, Paris, France., Delattre O; Genetics and Biology of Cancers Unit, Institut Curie, PSL Research University, Paris, France.; INSERM U830, Institut Curie Research Center, Paris, France.; Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France.; Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France.
المصدر: Nature genetics [Nat Genet] 2015 Sep; Vol. 47 (9), pp. 1073-8. Date of Electronic Publication: 2015 Jul 27.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: New York, NY : Nature Pub. Co., c1992-
مواضيع طبية MeSH: Bone Neoplasms/*genetics , Early Growth Response Protein 2/*genetics , Oncogene Proteins, Fusion/*genetics , Proto-Oncogene Protein c-fli-1/*genetics , RNA-Binding Protein EWS/*genetics , Sarcoma, Ewing/*genetics, Animals ; Base Sequence ; Bone Neoplasms/pathology ; Carotenoids/genetics ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Mice, SCID ; Microsatellite Repeats ; Molecular Sequence Data ; Neoplasm Transplantation ; Oxygenases/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Sarcoma, Ewing/pathology ; Tumor Burden
مستخلص: Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis.
التعليقات: Comment in: Nat Genet. 2015 Sep;47(9):964-5. (PMID: 26313223)
Comment in: Mol Cell Oncol. 2016 May;3(3):e1086853. (PMID: 27314638)
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معلومات مُعتمدة: U24 CA055727 United States CA NCI NIH HHS
المشرفين على المادة: 0 (EGR2 protein, human)
0 (EWS-FLI fusion protein)
0 (Early Growth Response Protein 2)
0 (Oncogene Proteins, Fusion)
0 (Proto-Oncogene Protein c-fli-1)
0 (RNA-Binding Protein EWS)
0 (beta-apocarotenoid-14',13'-dioxygenase)
36-88-4 (Carotenoids)
EC 1.13.- (Oxygenases)
تواريخ الأحداث: Date Created: 20150728 Date Completed: 20160113 Latest Revision: 20220317
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC4591073
DOI: 10.1038/ng.3363
PMID: 26214589
قاعدة البيانات: MEDLINE
الوصف
تدمد:1546-1718
DOI:10.1038/ng.3363