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

• DOI: 10.1007/s00401-023-02613-w
• Publication Date: 2023-07-26T17:36:36Z
• Authors: Leon D. Kaulen; Evgeniya Denisova; Felix Hinz; Ling Hai; Dennis Friedel; Octavian Henegariu; Dirk C. Hoffmann; Jakob Ito; Alexandros Kourte...; Pascal Lehnert; Sofia Doubrovinskaia; Philipp Karschnia; Louisa von Baumga...; Tobias Kessler; Joachim M. Baehring; Benedikt Brors; Felix Sahm; Wolfgang Wick
• Keywords: BCL6

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 lymphomagenesis remain unclear precluding molecular classification targeted therapies. In this study, comprehensive genetic analysis of 22 EBV PCNSL, therefore, integrated clinical pathological information with exome RNA sequencing (RNASeq) data. PCNSL germline controls carried median 55 protein-coding single nucleotide variants (SNVs; range 24–217) 2 insertions/deletions (range 0–22). landscape was largely shaped by aberrant somatic hypermutation 41.01% 31.79–53.49%) SNVs mapping to its target motifs. Tumors lacked established (MYD88, CD79B, PIM1) copy number (CDKN2A, HLA loss) driving − PCNSL. Instead, were characterized SOCS1 mutations (26%), predicted disinhibit JAK/STAT signaling, mutually exclusive gain-of-function NOTCH pathway (26%). Copy gains enriched on 11q23.3, locus directly for chromosomal aberrations EBV, includes SIK3 known protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical sensing viral DNA, 17q11 (NF1). Unsupervised clustering RNASeq data revealed two transcriptional groups, shared strong expression CD70 IL1R2, previously linked tolerogenic tumor microenvironments. Correspondingly, deconvolution bulk elevated M2-macrophage, T-regulatory cell, mast cell monocyte fractions in addition novel insights into the pathobiology provide rationale exploration therapies including JAK-, NOTCH- CD70-directed approaches.