DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.
Adenylate Kinase
/ genetics
Biomarkers, Tumor
/ genetics
Carcinoma
/ diagnosis
Choroid Plexus Neoplasms
/ diagnosis
CpG Islands
DNA Methylation
Diagnosis, Differential
Epigenesis, Genetic
Epigenomics
/ methods
Humans
Mutation
Papilloma, Choroid Plexus
/ diagnosis
Period Circadian Proteins
/ genetics
Phospholipid Transfer Proteins
/ genetics
Prognosis
Survival Analysis
Tumor Suppressor Protein p53
/ genetics
Choroid plexus tumors
DNA methylation
HumanMethylation450 arrays
Quantitative sodium bisulfite pyrosequencing
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
13 08 2019
13 08 2019
Historique:
received:
30
01
2019
accepted:
22
07
2019
entrez:
15
8
2019
pubmed:
15
8
2019
medline:
17
6
2020
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31409384
doi: 10.1186/s13148-019-0708-z
pii: 10.1186/s13148-019-0708-z
pmc: PMC6692938
doi:
Substances chimiques
Biomarkers, Tumor
0
PER2 protein, human
0
PLSCR4 protein, human
0
Period Circadian Proteins
0
Phospholipid Transfer Proteins
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Adenylate Kinase
EC 2.7.4.3
adenylate kinase 1
EC 2.7.4.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
117Subventions
Organisme : CIHR
ID : 6210100362
Pays : Canada
Commentaires et corrections
Type : ErratumIn
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