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Subependymal giant cell astrocytomas in Tuberous Sclerosis Complex have consistent TSC1/TSC2 biallelic inactivation, and no BRAF mutations

2017; Impact Journals LLC; Volume: 8; Issue: 56 Linguagem: Inglês

10.18632/oncotarget.20764

1949-2553

Anika Bongaarts, Krinio Giannikou, Roy J. Reinten, Jasper J. Anink, James D. Mills, Floor E. Jansen, Wim G.M. Spliet, Wilfred F.A. den Dunnen, Roland Coras, Ingmar Blümcke, Werner Paulus, Theresa O. Scholl, Martha Feucht, Katarzyna Kotulska, Sergiusz Jóźwiak, Anna Maria Buccoliero, Chiara Caporalini, Flavio Giordano, Lorenzo Genitori, Figen Söylemezoğlu, José Pimentel, Mark Nellist, Antoinette Y. N. Schouten–van Meeteren, Anwesha Nag, Angelika Mühlebner, David J. Kwiatkowski, Eleonora Aronica,

Epigenetics and DNA Methylation

// Anika Bongaarts 1, * , Krinio Giannikou 2, * , Roy J. Reinten 1 , Jasper J. Anink 1 , James D. Mills 1 , Floor E. Jansen 3 , Wim G.M. Spliet 4 , Willfred F.A. den Dunnen 5 , Roland Coras 6 , Ingmar Blümcke 6 , Werner Paulus 7 , Theresa Scholl 8 , Martha Feucht 8 , Katarzyna Kotulska 9 , Sergiusz Jozwiak 10 , Anna Maria Buccoliero 11 , Chiara Caporalini 11 , Flavio Giordano 12 , Lorenzo Genitori 12 , Figen Söylemezoğlu 13 , José Pimentel 14 , Mark Nellist 15 , Antoinette Y.N. Schouten-van Meeteren 16 , Anwesha Nag 17 , Angelika Mühlebner 1, 8 , David J. Kwiatkowski 2, ** and Eleonora Aronica 1, 18, 19 ** 1 Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 2 Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America 3 Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands 5 Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 6 Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany 7 Institute of Neuropathology, University Hospital Münster, Münster, Germany 8 Department of Pediatrics, Medical University of Vienna, Vienna, Austria 9 Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, Poland 10 Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland 11 Pathology Unit, Anna Meyer Children's Hospital, Florence, Italy 12 Department of Neurosurgery, Anna Meyer Children's Hospital, Florence, Italy 13 Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey 14 Department of Neurology, Hospital de Santa Maria, Lisbon, Portugal 15 Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands 16 Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 17 Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, Massachusetts, USA 18 Stichting Epilepsie Instellingen Nederland (SEIN), The Netherlands 19 Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands * These authors have contributed equally to this work ** These authors share the senior authorship Correspondence to: Eleonora Aronica, email: e.aronica@amc.uva.nl David J. Kwiatkowski, email: dk@rics.bwh.harvard.edu Keywords: SEGA; TSC; BRAF; loss of heterozygosity; low grade glioma Received: June 29, 2017 Accepted: July 31, 2017 Published: September 08, 2017 ABSTRACT Subependymal giant cell astrocytomas (SEGAs) are rare, low-grade glioneuronal brain tumors that occur almost exclusively in patients with tuberous sclerosis complex (TSC). Though histologically benign, SEGAs can lead to serious neurological complications, including hydrocephalus, intractable seizures and death. Previous studies in a limited number of SEGAs have provided evidence for a biallelic two-hit inactivation of either TSC1 or TSC2 , resulting in constitutive activation of the mechanistic target of rapamycin complex 1 pathway. The activating BRAF V600E mutation is a common genetic alteration in low grade gliomas and glioneuronal tumors, and has been reported in SEGAs as well. In the present study, we assessed the prevalence of the BRAF V600E mutation in a large cohort of TSC related SEGAs (n=58 patients including 56 with clinical TSC) and found no evidence of either BRAF V600E or other mutations in BRAF. To confirm that these SEGAs fit the classic model of two hit TSC1 or TSC2 inactivation, we also performed massively parallel sequencing of these loci. Nineteen (19) of 34 (56%) samples had mutations in TSC2 , 10 (29%) had mutations in TSC1 , while 5 (15%) had no mutation identified in TSC1 / TSC2. The majority of these samples had loss of heterozygosity in the same gene in which the mutation was identified. These results significantly extend previous studies, and in agreement with the Knudson two hit mechanism indicate that biallelic alterations in TSC2 and less commonly, TSC1 are consistently seen in SEGAs.