Oncotarget

Research Papers:

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

Anika Bongaarts, Krinio Giannikou, Roy J. Reinten, Jasper J. Anink, James D. Mills, Floor E. Jansen, Wim G.M. Spliet, Willfred F.A. den Dunnen, Roland Coras, Ingmar Blümcke, Werner Paulus, Theresa Scholl, Martha Feucht, Katarzyna Kotulska, Sergiusz Jozwiak, 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 _ and Eleonora Aronica

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Oncotarget. 2017; 8:95516-95529. https://doi.org/10.18632/oncotarget.20764

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Abstract

Anika Bongaarts1,*, Krinio Giannikou2,*, Roy J. Reinten1, Jasper J. Anink1, James D. Mills1, Floor E. Jansen3, Wim G.M. Spliet4, Willfred F.A. den Dunnen5, Roland Coras6, Ingmar Blümcke6, Werner Paulus7, Theresa Scholl8, Martha Feucht8, Katarzyna Kotulska9, Sergiusz Jozwiak10, Anna Maria Buccoliero11, Chiara Caporalini11, Flavio Giordano12, Lorenzo Genitori12, Figen Söylemezoğlu13, José Pimentel14, Mark Nellist15, Antoinette Y.N. Schouten-van Meeteren16, Anwesha Nag17, Angelika Mühlebner1,8, David J. Kwiatkowski2,** and Eleonora Aronica1,18,19**

1Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

2Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America

3Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, The Netherlands

4Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

5Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

6Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany

7Institute of Neuropathology, University Hospital Münster, Münster, Germany

8Department of Pediatrics, Medical University of Vienna, Vienna, Austria

9Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, Poland

10Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland

11Pathology Unit, Anna Meyer Children's Hospital, Florence, Italy

12Department of Neurosurgery, Anna Meyer Children's Hospital, Florence, Italy

13Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

14Department of Neurology, Hospital de Santa Maria, Lisbon, Portugal

15Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands

16Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

17Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, Massachusetts, USA

18Stichting Epilepsie Instellingen Nederland (SEIN), The Netherlands

19Swammerdam 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.


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