Distinct epigenetic and transcriptional profiles of Epstein-Barr virus-positive and negative primary CNS lymphomas

Ling Hai ^1,2, Dennis Friedel ^3,4, Felix Hinz ⁴

¹Clinical Cooperation Unit (CCU) Neuro-Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
²Department of Neurology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
³Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
⁴Department of Neuropathology, Heidelberg University Hospital, and Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
⁵Division of Applied Bioinformatics, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.
⁷Department of Neurosurgery, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
⁸Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
⁹Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

⁰Clinical Cooperation Unit (CCU) Neuro-Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Neuro-Oncology +

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November 22, 2024

View abstract on PubMed

Summary

Epstein-Barr virus (EBV)+ and EBV- primary CNS lymphomas (PCNSL) show distinct molecular profiles. These differences in gene expression and methylation highlight unique biological subtypes, informing potential targeted therapies for brain tumors.

Area Of Science

Neuro-oncology
Virology
Molecular Biology

Background

Epstein-Barr virus (EBV) presence defines distinct subtypes of primary CNS lymphoma (PCNSL).
Previous studies identified differing mutational landscapes between EBV+ and EBV- PCNSL.
Integrated transcriptional and epigenetic comparisons were lacking, hindering understanding of pathobiology and targeted therapy development.

Purpose Of The Study

To compare the integrated transcriptional and epigenetic profiles of EBV+ and EBV- PCNSL.
To identify molecular differences relevant for classification and targeted therapy.

Main Methods

RNA-sequencing and EPIC methylation arrays were performed on 38 PCNSL samples (15 EBV+, 23 EBV-).
Unsupervised clustering was used to analyze transcriptional and epigenetic data.
Differentially expressed and methylated genes were identified and integrated.

Main Results

Two distinct transcriptional clusters separated EBV+ and EBV- PCNSL, with EBV+ tumors showing upregulation of EBV-related genes and pathways like Interleukin-10 and NOTCH.
EBV- PCNSL exhibited enhanced B-cell receptor (BCR) and WNT/beta-catenin signaling.
Epigenetic profiling revealed reduced global promoter methylation in EBV+ PCNSL and distinct methylation clusters separating the two groups. Hypermethylation of CD79B correlated with its downregulation in EBV+ PCNSL.

Conclusions

EBV+ and EBV- PCNSL represent distinct biological subtypes with unique transcriptional and epigenetic signatures.
These molecular differences offer novel insights into PCNSL pathobiology.
Findings may guide the development of molecular diagnostics and targeted therapeutic strategies for PCNSL.

Keywords:

Epstein-Barr virus diffuse large B-cell lymphoma methylation primary CNS lymphoma transcriptomics