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Open Access 26-07-2023 | Lymphoma | Original Paper

Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas

Authors: Leon D. Kaulen, Evgeniya Denisova, Felix Hinz, Ling Hai, Dennis Friedel, Octavian Henegariu, Dirk C. Hoffmann, Jakob Ito, Alexandros Kourtesakis, Pascal Lehnert, Sofia Doubrovinskaia, Philipp Karschnia, Louisa von Baumgarten, Tobias Kessler, Joachim M. Baehring, Benedikt Brors, Felix Sahm, Wolfgang Wick

Published in: Acta Neuropathologica | Issue 3/2023

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Abstract

Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV+) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24–217) and 2 insertions/deletions (range 0–22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79–53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV PCNSL. Instead, EBV+ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+ PCNSL. In addition to novel insights into the pathobiology of EBV+ PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.
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Literature
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Metadata
Title
Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas
Authors
Leon D. Kaulen
Evgeniya Denisova
Felix Hinz
Ling Hai
Dennis Friedel
Octavian Henegariu
Dirk C. Hoffmann
Jakob Ito
Alexandros Kourtesakis
Pascal Lehnert
Sofia Doubrovinskaia
Philipp Karschnia
Louisa von Baumgarten
Tobias Kessler
Joachim M. Baehring
Benedikt Brors
Felix Sahm
Wolfgang Wick
Publication date
26-07-2023
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 3/2023
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-023-02613-w

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