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

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Abstract

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.

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Most cited references 31

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C11orf95-RELA fusions drive oncogenic NF-κB signaling in ependymoma

Matthew Parker, Kumarasamypet M. Mohankumar, Chandanamali Punchihewa … (2014)

The nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.

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Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes.

Pascal Johann, Serap Erkek, Marc Zapatka … (2016)

Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.

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ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma.

David E Reuss, Felix Sahm, Daniel Schrimpf … (2015)

Diffuse gliomas are represented in the 2007 WHO classification as astrocytomas, oligoastrocytomas and oligodendrogliomas of grades II and III and glioblastomas WHO grade IV. Molecular data on these tumors have a major impact on prognosis and therapy of the patients. Consequently, the inclusion of molecular parameters in the WHO definition of brain tumors is being planned and has been forwarded as the "ISN-Haarlem" consensus. We, here, analyze markers of special interest including ATRX, IDH and 1p/19q codeletion in a series of 405 adult patients. Among the WHO 2007 classified tumors were 152 astrocytomas, 61 oligodendrogliomas, 63 oligoastrocytomas and 129 glioblastomas. Following the concepts of the "ISN-Haarlem", we rediagnosed the series to obtain "integrated" diagnoses with 155 tumors being astrocytomas, 100 oligodendrogliomas and 150 glioblastomas. In a subset of 100 diffuse gliomas from the NOA-04 trial with long-term follow-up data available, the "integrated" diagnosis had a significantly greater prognostic power for overall and progression-free survival compared to WHO 2007. Based on the "integrated" diagnoses, loss of ATRX expression was close to being mutually exclusive to 1p/19q codeletion, with only 2 of 167 ATRX-negative tumors exhibiting 1p/19q codeletion. All but 4 of 141 patients with loss of ATRX expression and diffuse glioma carried either IDH1 or IDH2 mutations. Interestingly, the majority of glioblastoma patients with loss of ATRX expression but no IDH mutations exhibited an H3F3A mutation. Further, all patients with 1p/19 codeletion carried a mutation in IDH1 or IDH2. We present an algorithm based on stepwise analysis with initial immunohistochemistry for ATRX and IDH1-R132H followed by 1p/19q analysis followed by IDH sequencing which reduces the number of molecular analyses and which has a far better association with patient outcome than WHO 2007.

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Author and article information

Contributors

David Capper: david.capper@charite.de

Andreas von Deimling: Andreas.vondeimling@med.uni-heidelberg.de

Journal

Journal ID (nlm-ta): Acta Neuropathol

Journal ID (iso-abbrev): Acta Neuropathol

Title: Acta Neuropathologica

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0001-6322

ISSN (Electronic): 1432-0533

Publication date (Electronic): 2 July 2018

Publication date PMC-release: 2 July 2018

Publication date (Print): 2018

Volume: 136

Issue: 2

Pages: 181-210

Affiliations

[1 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Neuropathology, , University Hospital Heidelberg, ; Heidelberg, Germany

[2 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Clinical Cooperation Unit Neuropathology, , German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), ; Heidelberg, Germany

[3 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Department of Neuropathology, , Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, ; Berlin, Germany

[4 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), ; Heidelberg, Germany

[5 ]GRID grid.461742.2, Hopp Children’s Cancer Center, at the NCT Heidelberg (KiTZ), ; Heidelberg, Germany

[6 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Pediatric Glioma Research Group, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany

[7 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Pediatric Neurooncology, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany

[8 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Pathology and Center for Cancer Research, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA 02114 USA

[9 ]GRID grid.66859.34, Broad Institute of Harvard and MIT, ; Cambridge, MA 02142 USA

[10 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Department of Neurosurgery, University Medical Center Mannheim, , University of Heidelberg, ; Mannheim, Germany

[11 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Neurosurgery, , Heidelberg University Hospital, ; Heidelberg, Germany

[12 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, , German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), ; Heidelberg, Germany

[13 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, , Heidelberg University, ; Mannheim, Germany

[14 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Neurology, , Heidelberg University Hospital, ; Heidelberg, Germany

[15 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, , Heidelberg University Hospital, ; Heidelberg, Germany

[16 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, CCU Pediatric Oncology (G340), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), ; Heidelberg, Germany

[17 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of General Pathology, Institute of Pathology, , Heidelberg University Hospital, ; Heidelberg, Germany

[18 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Clinical Cooperation Unit Neurooncology, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany

Article

Publisher ID: 1879

DOI: 10.1007/s00401-018-1879-y

PMC ID: 6060790

PubMed ID: 29967940

SO-VID: d6e34a42-1a3a-4960-a4e9-0c14b97cb9e3

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 1 June 2018

Date revision received : 22 June 2018

Date accepted : 22 June 2018

Funding

Funded by: DKFZ-HIPO_036

Funded by: German Childhood Cancer Foundation

Funded by: Illumina Medical Research Grant

Funded by: DKTK joint funding project ‘Next Generation Molecular Diagnostics of Malignant Gliomas’

Funded by: A Kids’ Brain Tumour Cure (PLGA) Foundation

Funded by: Brain Tumour Charity (UK)

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ScienceOpen disciplines: Neurology

Keywords: dna methylation,epic array,tumor classification,copy-number variation

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ScienceOpen disciplines: Neurology

Keywords: dna methylation, epic array, tumor classification, copy-number variation

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

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Karger: Neurology and Neuroscience

Most cited references 31

C11orf95-RELA fusions drive oncogenic NF-κB signaling in ependymoma

Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes.

ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma.

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