Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups

Thomas, Christian; Sill, Martin; Ruland, Vincent; Witten, Anika; Hartung, Stefan; Kordes, Uwe; Jeibmann, Astrid; Beschorner, Rudi; Keyvani, Kathy; Bergmann, Markus; Mittelbronn, Michel; Pietsch, Torsten; Felsberg, Jörg; Monoranu, Camelia; Varlet, Pascale; Hauser, Péter; Olar, Adriana; Grundy, Richard G.; Wolff, Johannes; Korshunov, Andrey; Jones, David; Bewerunge-Hudler, Melanie; Hovestadt, Volker; Deimling, Andreas von; Pfister, Stefan M.; Paulus, Werner; Capper, David; Hasselblatt, Martin

doi:10.1093/neuonc/nov322

Cited by 77 publications

(64 citation statements)

References 17 publications

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“…Three subclasses exist, “plexus tumor, subclass adult”, “plexus tumor, subclass pediatric A”, and “plexus tumor, subclass pediatric B” that broadly correspond to the three previously defined methylation clusters [50]. “Plexus tumor, subclass adult” predominantly contains adolescent and adult patients with choroid plexus papilloma and a fraction of approximately 15% of atypical plexus papilloma.…”

Section: Resultsmentioning

confidence: 99%

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

et al. 2018

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Recently, we described a machine learning approach for classification of central nervous system tumors based on the analysis of genome-wide DNA methylation patterns [6]. Here, we report on DNA methylation-based central nervous system (CNS) tumor diagnostics conducted in our institution between the years 2015 and 2018. In this period, more than 1000 tumors from the neurosurgical departments in Heidelberg and Mannheim and more than 1000 tumors referred from external institutions were subjected to DNA methylation analysis for diagnostic purposes. We describe our current approach to the integrated diagnosis of CNS tumors with a focus on constellations with conflicts between morphological and molecular genetic findings. We further describe the benefit of integrating DNA copy-number alterations into diagnostic considerations and provide a catalog of copy-number changes for individual DNA methylation classes. We also point to several pitfalls accompanying the diagnostic implementation of DNA methylation profiling and give practical suggestions for recurring diagnostic scenarios.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1879-y) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

et al. 2018

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“…Cluster three (young age and supratentorial location) contained CP tumors with a higher risk of progression and high p53 overexpression; CP carcinomas were only presented in this cluster and comprised 62% of this cluster. The data clearly highlight the potential of molecular profiling and p53 status to provide additional layers of information to improve risk stratification in CP tumors, including CP carcinomas in particular …”

Section: Biology and Molecular Findingsmentioning

confidence: 91%

“…Additionally, Thomas et al. have described a series of 92 patients with CP tumors in whom genome‐wide methylation profiling and unsupervised hierarchical cluster analysis led to the identification of three distinct molecular subgroups (clusters 1–3) . Cluster three (young age and supratentorial location) contained CP tumors with a higher risk of progression and high p53 overexpression; CP carcinomas were only presented in this cluster and comprised 62% of this cluster.…”

Section: Biology and Molecular Findingsmentioning

confidence: 99%

Pediatric choroid plexus carcinoma: Biologically and clinically in need of new perspectives

Zaky

Finlay

2018

Pediatric Blood & Cancer

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Choroid plexus (CP) carcinoma is a rare pediatric brain neoplasm. Recent studies have highlighted the potential of genome-wide methylation and gene expression profiling to provide additional layers of information to improve tumor risk-stratification. There is a lack of data regarding the best therapy, and approaches have been heterogeneous. Despite multidisciplinary treatment approaches, the outcome remains guarded and treatments have been based on case series and expert opinions. In this study, we discuss the recent wealth of data regarding CP carcinoma molecular biology and current management. We also briefly highlight the remaining barriers to formulate the best treatment strategies, and future therapeutic potentials.

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“…Cross-validation of the RF classifier resulted in an estimated error rate of 4.89% for raw and 4.28% for calibrated scores and an area under receiver operating characteristic curve (AUC) of 0.99, indicating a high discriminating power (Figure 2b, Extended Data Figure 5c). The vast majority of cross-validation misclassifications occurred within eight groups of histologically and biologically closely related tumour classes, distinction of which is currently without clinical impact (with the possible exception of choroid plexus tumours 13 ; Figure 2b). We therefore defined eight ‘methylation class families’ (MCF), for which calibrated scores are summed up to a single score.…”

Section: Classifier Developmentmentioning

confidence: 99%

DNA methylation-based classification of central nervous system tumours

Capper

Jones

Sill

et al. 2018

Nature

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Summary Accurate pathological diagnosis is crucial for optimal management of cancer patients. For the ~100 known central nervous system (CNS) tumour entities, standardization of the diagnostic process has been shown to be particularly challenging - with substantial inter-observer variability in the histopathological diagnosis of many tumour types. We herein present the development of a comprehensive approach for DNA methylation-based CNS tumour classification across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that availability of this method may have substantial impact on diagnostic precision compared with standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility we have designed a free online classifier tool (www.molecularneuropathology.org) requiring no additional onsite data processing. Our results provide a blueprint for the generation of machine learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

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Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups

Cited by 77 publications

References 17 publications

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

Pediatric choroid plexus carcinoma: Biologically and clinically in need of new perspectives

DNA methylation-based classification of central nervous system tumours

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