Abstract

Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.

Details

Title
Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma
Author
Snuderl, Matija 1 ; Kasthuri Kannan 2   VIAFID ORCID Logo  ; Pfaff, Elke 3 ; Wang, Shiyang 4 ; Stafford, James M 5 ; Serrano, Jonathan 6 ; Heguy, Adriana 7 ; Ray, Karina 6 ; Faustin, Arline 8 ; Aminova, Olga 6 ; Dolgalev, Igor 9   VIAFID ORCID Logo  ; Stapleton, Stacie L 10 ; Zagzag, David 11 ; Chiriboga, Luis 12   VIAFID ORCID Logo  ; Gardner, Sharon L 13 ; Wisoff, Jeffrey H 14 ; Golfinos, John G 15 ; Capper, David 16 ; Hovestadt, Volker 17 ; Rosenblum, Marc K 18 ; Placantonakis, Dimitris G 19 ; LeBoeuf, Sarah E 12 ; Papagiannakopoulos, Thales Y 12 ; Chavez, Lukas 20   VIAFID ORCID Logo  ; Sama Ahsan 21 ; Eberhart, Charles G 22 ; Pfister, Stefan M 3 ; Jones, David T W 23 ; Karajannis, Matthias A 24   VIAFID ORCID Logo 

1  Division of Neuropathology, NYU Langone Health, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; Department of Neurology, NYU Langone Health, New York, NY, USA; Department of Pathology, NYU Langone Health, New York, NY, USA 
2  Division of Neuropathology, NYU Langone Health, New York, NY, USA; Department of Pathology, NYU Langone Health, New York, NY, USA 
3  Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg, University Hospital, Heidelberg, Germany 
4  Division of Pediatric Hematology/Oncology, NYU Langone Health, New York, NY, USA 
5  Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY, USA 
6  Genome Technology Center, NYU Langone Health, New York, NY, USA 
7  Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; Department of Pathology, NYU Langone Health, New York, NY, USA; Genome Technology Center, NYU Langone Health, New York, NY, USA 
8  Department of Neurology, NYU Langone Health, New York, NY, USA; Department of Pathology, NYU Langone Health, New York, NY, USA 
9  Department of Pathology, NYU Langone Health, New York, NY, USA; Genome Technology Center, NYU Langone Health, New York, NY, USA 
10  Johns Hopkins All Children’s Hospital, Cancer and Blood Disorders Institute, St Petersburg, FL, USA 
11  Division of Neuropathology, NYU Langone Health, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; Department of Neurosurgery, NYU Langone Health, New York, NY, USA 
12  Department of Pathology, NYU Langone Health, New York, NY, USA 
13  Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; Division of Pediatric Hematology/Oncology, NYU Langone Health, New York, NY, USA 
14  Department of Neurosurgery, NYU Langone Health, New York, NY, USA; Division of Pediatric Neurosurgery, NYU Langone Health, New York, NY, USA 
15  Department of Neurosurgery, NYU Langone Health, New York, NY, USA 
16  Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Charité — Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany 
17  Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany 
18  Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 
19  Johns Hopkins All Children’s Hospital, Cancer and Blood Disorders Institute, St Petersburg, FL, USA; Neuroscience Institute and Kimmel Center for Stem Cell Biology, NYU Langone Health, New York, NY, USA 
20  Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 
21  Division of Pediatric Oncology, Johns Hopkins Hospital, Baltimore, MD, USA 
22  Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA 
23  Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 
24  Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 
Pages
1-10
Publication year
2018
Publication date
Jul 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-05029-3
ProQuest document ID
2072696490
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.