DNA methylation signature is prognostic of choroid plexus tumor aggressiveness

Autor: Michael Brudno, Jonathan L. Finlay, Andrei L. Turinsky, Rosanna Weksberg, Martin Sill, Christian Thomas, Sanaa Choufani, Uri Tabori, Eric Bouffet, Nada Jabado, Cynthia Hawkins, Malgorzata Pienkowska, Adam Shlien, David Capper, Diana M. Merino, Ana Novokmet, Tanya Guha, Richard J. Gilbertson, Martin Hasselblatt, David Malkin
Přispěvatelé: Malkin, David [0000-0001-5752-9763], Apollo - University of Cambridge Repository
Rok vydání: 2019
Předmět:
Epigenomics
0301 basic medicine
Oncology
Choroid Plexus Neoplasms
medicine.medical_specialty
Epigenesis
Genetic
Diagnosis
Differential
03 medical and health sciences
Cancer epigenetics and diagnostics
0302 clinical medicine
Choroid plexus tumors
Internal medicine
HumanMethylation450 arrays
Biomarkers
Tumor
Genetics
medicine
Humans
Phospholipid Transfer Proteins
Choroid plexus tumor
Molecular Biology
Genetics (clinical)
DNA methylation
business.industry
Research
Adenylate Kinase
Carcinoma
dNaM
Period Circadian Proteins
Choroid plexus carcinoma
Prognosis
medicine.disease
Survival Analysis
Choroid plexus papilloma
Human genetics
3. Good health
030104 developmental biology
CpG site
030220 oncology & carcinogenesis
Mutation
Quantitative sodium bisulfite pyrosequencing
CpG Islands
Papilloma
Choroid Plexus
Choroid plexus
Tumor Suppressor Protein p53
business
Developmental Biology
Zdroj: Clinical Epigenetics
ISSN: 1868-7083
1868-7075
Popis: 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. Electronic supplementary material The online version of this article (10.1186/s13148-019-0708-z) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
Externí odkaz: