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Cancer Res. 2019 May 1;79(9):2208-2219. doi: 10.1158/0008-5472.CAN-18-2565. Epub 2019 Mar 18.

Myc and Loss of p53 Cooperate to Drive Formation of Choroid Plexus Carcinoma.

Author information

1
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
2
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
3
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
4
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
5
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
6
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
7
Bioinformatics Core Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
8
Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles.
9
Department of Chemistry, The Scripps Research Institute, La Jolla, California.
10
Department of Immunology, The Scripps Research Institute, La Jolla, California.
11
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California.
12
Division of Neurosurgery and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
13
Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
14
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
15
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
16
UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
17
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
18
Molecular and Medical Genetics Department, Oregon Health and Sciences University, Portland, Oregon.
19
Cancer Research UK Cambridge Centre, CRUK Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
20
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. rwreya@sbpdiscovery.org.

Abstract

Choroid plexus carcinoma (CPC) is a rare brain tumor that occurs most commonly in very young children and has a dismal prognosis despite intensive therapy. Improved outcomes for patients with CPC depend on a deeper understanding of the mechanisms underlying the disease. Here we developed transgenic models of CPCs by activating the Myc oncogene and deleting the Trp53 tumor suppressor gene in murine neural stem cells or progenitors. Murine CPC resembled their human counterparts at a histologic level, and like the hypodiploid subset of human CPC, exhibited multiple whole-chromosome losses, particularly of chromosomes 8, 12, and 19. Analysis of murine and human CPC gene expression profiles and copy number changes revealed altered expression of genes involved in cell cycle, DNA damage response, and cilium function. High-throughput drug screening identified small molecule inhibitors that decreased the viability of CPC. These models will be valuable tools for understanding the biology of choroid plexus tumors and for testing novel approaches to therapy. SIGNIFICANCE: This study describes new mouse models of choroid plexus carcinoma and uses them to investigate the biology and therapeutic responsiveness of this highly malignant pediatric brain tumor.

PMID:
30885981
PMCID:
PMC6497574
[Available on 2020-05-01]
DOI:
10.1158/0008-5472.CAN-18-2565

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