Oncotarget

Research Papers:

Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

Adam M. Fontebasso, Margret Shirinian, Dong-Anh Khuong-Quang, Denise Bechet, Tenzin Gayden, Marcel Kool, Nicolas De Jay, Karine Jacob, Noha Gerges, Barbara Hutter, Huriye Şeker-Cin, Hendrik Witt, Alexandre Montpetit, Sébastien Brunet, Pierre Lepage, Geneviève Bourret, Almos Klekner, László Bognár, Peter Hauser, Miklós Garami, Jean-Pierre Farmer, Jose-Luis Montes, Jeffrey Atkinson, Sally Lambert, Tony Kwan, Andrey Korshunov, Uri Tabori, V. Peter Collins, Steffen Albrecht, Damien Faury, Stefan M. Pfister, Werner Paulus, Martin Hasselblatt, David T.W. Jones, Nada Jabado _

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Oncotarget. 2015; 6:31844-31856. https://doi.org/10.18632/oncotarget.5571

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Abstract

Adam M. Fontebasso1,*, Margret Shirinian2,*, Dong-Anh Khuong-Quang3, Denise Bechet3, Tenzin Gayden3, Marcel Kool3, Nicolas De Jay3, Karine Jacob3, Noha Gerges3, Barbara Hutter5, Huriye Şeker-Cin4, Hendrik Witt4,6, Alexandre Montpetit7, Sébastien Brunet7, Pierre Lepage7, Geneviève Bourret7, Almos Klekner8, László Bognár8, Peter Hauser9, Miklós Garami9, Jean-Pierre Farmer10, Jose-Luis Montes10, Jeffrey Atkinson10, Sally Lambert11, Tony Kwan7, Andrey Korshunov12, Uri Tabori13, V. Peter Collins11, Steffen Albrecht14, Damien Faury3, Stefan M. Pfister4,6, Werner Paulus15, Martin Hasselblatt15, David T.W. Jones4 and Nada Jabado1,3

1 Division of Experimental Medicine, McGill University and McGill University Health Centre, Montreal, Quebec, Canada

2 Department of Experimental Pathology, Immunology and Microbiology, American University Of Beirut, Beirut, Lebanon

3 Departments of Pediatrics and Human Genetics, McGill University and McGill University Health Centre, Montreal, Quebec, Canada

4 Division of Pediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany

5 Division of Theoretical Bioinformatics, German Cancer Research Centre (DKFZ), Heidelberg, Germany

6 Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany

7 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada

8 Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

9 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary

10 Department of Neurosurgery, Montreal Children’s Hospital and McGill University Health Centre, Montreal, Canada

11 Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom

12 Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany

13 Division of Pediatric Hematology-Oncology and The Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada

14 Department of Pathology, Montreal Children’s Hospital and McGill University Health Centre, Montreal, Canada

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

* These authors have contributed equally to this work

Correspondence to:

Nada Jabado, email:

David T.W. Jones, email:

Keywords: pilocytic astrocytoma, aneuploidy, BRAF, MDM2, PLK2, aging

Received: June 07, 2015 Accepted: August 15, 2015 Published: September 10, 2015

Abstract

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.


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