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

被引：8

作者：

Kaulen, Leon D. ^{[1
,2
,3
]}

Denisova, Evgeniya ^{[4
,5
]}

Hinz, Felix ^{[6
,7
,8
]}

Hai, Ling ^{[2
,3
]}

Friedel, Dennis ^{[6
]}

Henegariu, Octavian ^{[9
,10
]}

Hoffmann, Dirk C. ^{[1
,2
,3
,11
]}

Ito, Jakob ^{[2
,3
]}

Kourtesakis, Alexandros ^{[2
,3
]}

Lehnert, Pascal ^{[2
,3
]}

Doubrovinskaia, Sofia ^{[1
]}

Karschnia, Philipp ^{[12
,13
]}

von Baumgarten, Louisa ^{[12
,13
]}

Kessler, Tobias ^{[1
,2
,3
]}

Baehring, Joachim M. ^{[9
,14
]}

Brors, Benedikt ^{[4
,5
]}

Sahm, Felix ^{[6
,7
,8
]}

Wick, Wolfgang ^{[1
,2
,3
]}

机构：

[1] Heidelberg Univ, Univ Hosp Heidelberg, Dept Neurol, Heidelberg, Germany

[2] German Canc Res Ctr, Clin Cooperat Unit CCU Neurooncol, Neuenheimer Feld 400, D-69120 Heidelberg, Germany

[3] German Consortium Translat Canc Res DKTK, Neuenheimer Feld 400, D-69120 Heidelberg, Germany

[4] German Canc Res Ctr, German Consortium Translat Canc Res DKTK, Div Appl Bioinformat, Heidelberg, Germany

[5] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[6] Heidelberg Univ Hosp, Dept Neuropathol, Heidelberg, Germany

[7] German Canc Res Ctr, Clin Cooperat Unit CCU Neuropathol, Heidelberg, Germany

[8] German Consortium Translat Canc Res DKTK, Heidelberg, Germany

[9] Yale Sch Med, Dept Neurosurg, New Haven, CT USA

[10] Yale Sch Med, Dept Genet, New Haven, CT USA

[11] Heidelberg Univ, Fac Biosci, Heidelberg, Germany

[12] Ludwig Maximilians Univ LMU Munich, Munich Univ Hosp, Dept Neurosurg, Munich, Germany

[13] German Canc Consortium DKTK, Partner Site, Munich, Germany

[14] Yale Sch Med, Dept Neurol, New Haven, CT USA

来源：

ACTA NEUROPATHOLOGICA | 2023年 / 146卷 / 03期

关键词：

Primary CNS lymphoma; Non-Hodgkin lymphoma; Epstein-Barr virus; Genetics; Exome sequencing; RNA sequencing; Immunodeficiency; CENTRAL-NERVOUS-SYSTEM; HODGKIN LYMPHOMA; T-CELLS; MUTATIONS; CLASSIFICATION; RUXOLITINIB; ACTIVATION; SIGNATURES; ALIGNMENT; SURVIVAL;

D O I：

10.1007/s00401-023-02613-w

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：499 / 514

页数：16