DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis

TY - JOUR

T1 - DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis

AU - Sahm, Felix

AU - Schrimpf, Daniel

AU - Stichel, Damian

AU - Jones, David T W

AU - Hielscher, Thomas

AU - Schefzyk, Sebastian

AU - Okonechnikov, Konstantin

AU - Koelsche, Christian

AU - Reuss, David E

AU - Capper, David

AU - Sturm, Dominik

AU - Wirsching, Hans-Georg

AU - Berghoff, Anna Sophie

AU - Baumgarten, Peter

AU - Kratz, Annekathrin

AU - Huang, Kristin

AU - Wefers, Annika K

AU - Hovestadt, Volker

AU - Sill, Martin

AU - Ellis, Hayley P

AU - Kurian, Kathreena M

AU - Okuducu, Ali Fuat

AU - Jungk, Christine

AU - Drueschler, Katharina

AU - Schick, Matthias

AU - Bewerunge-Hudler, Melanie

AU - Mawrin, Christian

AU - Seiz-Rosenhagen, Marcel

AU - Ketter, Ralf

AU - Simon, Matthias

AU - Westphal, Manfred

AU - Lamszus, Katrin

AU - Becker, Albert

AU - Koch, Arend

AU - Schittenhelm, Jens

AU - Rushing, Elisabeth J

AU - Collins, V Peter

AU - Brehmer, Stefanie

AU - Chavez, Lukas

AU - Platten, Michael

AU - Hänggi, Daniel

AU - Unterberg, Andreas

AU - Paulus, Werner

AU - Wick, Wolfgang

AU - Pfister, Stefan M

AU - Mittelbronn, Michel

AU - Preusser, Matthias

AU - Herold-Mende, Christel

AU - Weller, Michael

AU - von Deimling, Andreas

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2017/5

Y1 - 2017/5

N2 - BACKGROUND: The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups.METHODS: In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip.FINDINGS: We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma.INTERPRETATION: DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma.FUNDING: German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.

AB - BACKGROUND: The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups.METHODS: In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip.FINDINGS: We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma.INTERPRETATION: DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma.FUNDING: German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.

KW - DNA Copy Number Variations

KW - DNA Methylation

KW - DNA Mutational Analysis

KW - DNA-Binding Proteins

KW - Disease Progression

KW - Disease-Free Survival

KW - Female

KW - Genome

KW - Humans

KW - Kruppel-Like Transcription Factors

KW - Male

KW - Meningeal Neoplasms

KW - Meningioma

KW - Neoplasm Grading

KW - Neoplasm Recurrence, Local

KW - Neurofibromin 2

KW - Nuclear Proteins

KW - Proto-Oncogene Proteins c-akt

KW - Retrospective Studies

KW - Sequence Analysis, RNA

KW - Smoothened Receptor

KW - Survival Rate

KW - Transcription Factors

KW - Transcriptome

KW - Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

KW - Journal Article

KW - Multicenter Study

U2 - 10.1016/S1470-2045(17)30155-9

DO - 10.1016/S1470-2045(17)30155-9

M3 - SCORING: Journal article

C2 - 28314689

VL - 18

SP - 682

EP - 694

JO - LANCET ONCOL

JF - LANCET ONCOL

SN - 1470-2045

IS - 5

ER -