DNA methylation signature is prognostic of choroid plexus tumor aggressiveness

Jonathan L Finlay,David Malkin,Éric Bouffet ,Sanaa Choufani,Tanya Guha,Małgorzata Pieńkowska ,David Capper,Rosanna Weksberg,Richard J Gilbertson,Cynthia Hawkins,Nada Jabado,Martin Hasselblatt,Andrei L Turinsky,Ana Novokmet,Christian Thomas,Uri Tabori,Michael Brudno,Diana M Merino,Martin Sill,Adam Shlien

doi:10.1186/s13148-019-0708-z

Abstract

BackgroundHistological 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.MethodsWe 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.ResultsGenerated 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.ConclusionsWe 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.

Highlights

Choroid plexus tumors (CPTs) are rare neoplasms of the central nervous system
Identification of methylation signature for choroid plexus carcinoma (CPC) and TP53 mutation groups in CPCs Analysis of the genome-wide DNA methylation (DNAm) of primary choroid plexus tumors (CPTs) did not show significant differences between choroid plexus papilloma (CPP) and atypical choroid plexus papilloma (aCPP) (Mann–Whitney p value ≥ 0.55 after FDR correction in all 485577 CpG probes) but there was a significant difference in the CpG methylation profile between CPCs and CPPs or aCPPs (Mann–Whitney p value ≤ 0.048, FDR corrected in 51479 CpG sites)
There were no significant differences in genome-wide DNAm between CPPs and aCPPs, there was a CPC-specific signature in comparison to CPP

Summary

Introduction

Choroid plexus tumors (CPTs) are rare neoplasms of the central nervous system. Within this family of tumors, choroid plexus carcinoma (CPC) is a malignant neoplasm, categorized as a grade III tumor by the World Health Organization (WHO). Overall long-term survival for CPPs is relatively favorable (85–100%) after surgical resection alone, CPCs are significantly more aggressive, with a greater tendency for recurrence and less than 50% of patients survive even in the context of combined surgery, chemo- and radiation therapy [3,4,5,6] Most of these children are younger than 3 years of age, and the long-term damaging effects of this therapy on growth and the developing brain are of immense concern, highlighting the need for better biologic risk stratification for tumors in these young patients. 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); these distinctions can be challenging. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs

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