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Clin Epigenetics. 2019 Aug 13;11(1):117. doi: 10.1186/s13148-019-0708-z.

DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.

Author information

1
Genetics and Genome Biology Program, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.
2
Center for Computational Medicine, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.
3
Friends of Cancer Research, 1800 M Street, NW, Suite 1050 South, Washington, DC, 20036, USA.
4
Department of Computer Science, University of Toronto, 40 St. George Street, Toronto, Ontario, M5S 2E4, Canada.
5
Division of Clinical and Metabolic Genetics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.
6
Department of Pediatrics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.
7
Paediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.
8
Division of Hematology/Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.
9
Department of Oncology, Cambridge Cancer Center, Robinson Way, Cambridge, CB2 0RE, England.
10
Neuro-Oncology Program, Nationwide Children's Hospital and The Ohio State University, 700 Children's Dr, Columbus, OH, 43205, USA.
11
Division of Hematology/Oncology, Montreal Children's Hospital of the McGill University Health Centre (RI-MUHC), 1001 Decarie Blvd, Montreal, Québec, H4A 3 J1, Canada.
12
Institute of Neuropathology, University Hospital Münster, 48149, Münster, Germany.
13
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
14
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
15
Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Charitéplatz 1, 10117, Berlin, Germany.
16
German Cancer Consortium (DKTK), Partner Site Berlin, Invalidenstrasse 80, 10117, Berlin, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
17
Genetics and Genome Biology Program, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada. david.malkin@sickkids.ca.
18
Division of Hematology/Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. david.malkin@sickkids.ca.
19
Department of Pediatrics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. david.malkin@sickkids.ca.
20
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario, M5G 1 L7, Canada. david.malkin@sickkids.ca.

Abstract

BACKGROUND:

Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child's brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs.

METHODS:

We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany.

RESULTS:

Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment.

CONCLUSIONS:

We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management.

KEYWORDS:

Choroid plexus tumors; DNA methylation; HumanMethylation450 arrays; Quantitative sodium bisulfite pyrosequencing

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