Comprehensive phenotypic characterization of PTLD reveals potential reliance on EBV or NF‐κB signalling instead of B‐cell receptor signalling

Menter, Thomas; Dickenmann, Michael; Juškevičius, Darius; Steiger, Juerg; Dirnhofer, Stephan; Tzankov, Alexandar

doi:10.1002/hon.2280

Cited by 12 publications

(12 citation statements)

References 45 publications

(51 reference statements)

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“…The differences in the frequencies were more significant when compared to our IC‐DLBCL cohort than to the COSMIC database (Forbes et al , ). As SOCS1 is involved in JAK/STAT signalling (Sasaki et al , ), the lack of SOCS1 mutations further corroborates our previous findings that perturbation of JAK/STAT pathway may not be a common pathogenetic mechanism in PT‐DLBCL (Menter et al , ). The lack of CARD11 mutations in PT‐DLBCL suggests possible alternate mechanisms for activation of NF‐κB signalling in this entity (discussed in more detail in the next paragraph).…”

Section: Discussionsupporting

confidence: 89%

“…A detailed list of mutational frequencies can be found in the supplementary files. Mutations , 1999), the lack of SOCS1 mutations further corroborates our previous findings that perturbation of JAK/ STAT pathway may not be a common pathogenetic mechanism in PT-DLBCL (Menter et al, 2016). The lack of CARD11 mutations in PT-DLBCL suggests possible alternate mechanisms for activation of NF-jB signalling in this entity (discussed in more detail in the next paragraph).…”

Section: Discussionsupporting

confidence: 86%

“…The reduced frequency of mutations related to NF‐κB signalling in EBV + PT‐DLBCL provides further support to our hypothesis. This is substantiated by our previous study, which documented the lack of expression of NF‐κB signalling‐related proteins in EBV + PT‐DLBCL (Menter et al , ). Analogously, investigations on EBV‐associated DLBCL of the elderly have also shown lower mutation frequencies in NF‐κB pathway‐related genes (Gebauer et al , ).…”

Section: Discussionsupporting

confidence: 78%

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Mutational landscape of B‐cell post‐transplant lymphoproliferative disorders

et al. 2017

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It is currently unclear whether post-transplant diffuse large B-cell lymphomas (PT-DLBCL) display a similar genomic landscape as DLBCL in immunocompetent patients (IC-DLBCL). We investigated 50 post-transplant lymphoproliferative disorders (PTLDs) including 37 PT-DLBCL samples for somatic mutations frequently observed in IC-DLBCL. Targeted Next Generation Sequencing (NGS) using the Ion Torrent platform and a customized panel of 68 genes was performed on genomic DNA. Non-tumoural tissue was sequenced to exclude germline variants in cases where available. A control cohort of 76 IC-DLBCL was available for comparative analyses. In comparison to IC-DLBCLs, PT-DLBCL showed more frequent mutations of TP53 (P = 0·004), and absence of ATM and B2M mutations (P = 0·004 and P = 0·016, respectively). In comparison to IC-DLBCLs, Epstein-Barr virus (EBV) PT-DLBCL had fewer mutated genes (P = 0·007) and particularly fewer mutations in nuclear factor-κB pathway-related genes (P = 0·044). TP53 mutations were more frequent in EBV PT-DLBCL as compared to IC-DLBCL (P = 0·001). Germinal centre B cell (GCB) subtype of PT-DLBCL had fewer mutations and mutated genes than GCB-IC-DLBCLs (P = 0·048 and 0·04 respectively). Polymorphic PTLD displayed fewer mutations as compared to PT-DLBCL (P = 0·001). PT-DLBCL differs from IC-DLBCL with respect to mutations in genes related to DNA damage control and immune-surveillance, and EBV association is likely to have a bearing on the mutational pattern.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 78%

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Mutational landscape of B‐cell post‐transplant lymphoproliferative disorders

et al. 2017

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“…The programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis, which plays an important role both in transplanted organ tolerance and in antitumour immune responses, has been studied in different haematological neoplasms . Nevertheless, its clinical and biological significance in PTLD is largely unknown …”

Section: Introductionmentioning

confidence: 99%

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in post‐transplant lymphoproliferative disorders: association with Epstein–Barr virus, PD‐L1 copy number alterations, and outcome

et al. 2019

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Aims The clinical implications of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in patients with post‐transplant lymphoproliferative disorders are largely unknown, and its association with Epstein–Barr virus (EBV) status and PD‐L1 copy number alterations (CNAs) has not been thoroughly studied. Methods and results PD1/PD‐L1 expression was studied in 50 adult post‐transplant lymphoproliferative disorders, and the correlations with PD‐L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty‐seven (74%) cases were classified as diffuse large B‐cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty‐four cases were EBV‐positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD‐L1 expression in tumour cells and tumour‐associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD‐L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non‐germinal centre type DLBCL (P < 0.001). Cases with PD‐L1‐positive tumour cells showed a higher number of PD‐L1 CNAs than PD‐L1‐negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD‐L1 expression showed the worst overall survival (P < 0.001). Conclusions The PD1/PD‐L1 axis is deregulated in post‐transplant lymphoproliferative disorders, with frequent PD‐L1 expression and PD1 negativity. PD‐L1 expression is associated with EBV latency II or III and PD‐L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD‐L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.

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“…EBV expression was unrelated to PTLD-related EFS or OS. CD20 expression is thus [12]. EBV and NF-kappaB are important drivers in PTLD in contrast to B-cell receptor signaling.…”

Section: Cd20 Positivitymentioning

confidence: 99%

Clinical and Pathological Review of Post Transplant Lymphoproliferative Disorders

Naik¹,

Zheng²,

Rakszawski³

et al. 2018

Organ Donation and Transplantation - Current Status and Future Challenges

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Posttransplant lymphoproliferative disorder (PTLD) is a rare but potentially serious complication following transplantation with an overall incidence of PTLD of 1-5% in solid organ transplant (SOT) recipients and 1% in hematopoietic stem cell transplant (HSCT) recipients. The clinical and pathological spectrum of PTLD is broad; however, most cases of PTLD occur within the first year after transplantation and are associated with EBV. Clinical features that independently predict rates of response and survival have not been systematically studied for PTLD. Patients whose PTLD expressed CD20 or EBV have shorter intervals to PTLD onset, whereas late-onset cases of PTLD are typically EBV negative. Phenotypic characterization of PTLD reveals potential reliance on EBV or NF-kappaB signaling instead of B-cell receptor signaling, which links PTLD to other subgroups of EBV-related lymphomas, highlighting new potential treatment approaches. PTLD can be a life-threatening post-HSCT complication due to the impact of the patient's underlying disease (malignant or nonmalignant) as well as the type and intensity of the conditioning regimen. EBV-negative PTLD is more often a delayed phenomenon post-HSCT compared to EBV-positive PTLD. Further investigations are needed to better under stand the role of EBV in the pathogenesis of different forms of PTLD in the immunosuppressed patients.

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Comprehensive phenotypic characterization of PTLD reveals potential reliance on EBV or NF‐κB signalling instead of B‐cell receptor signalling

Cited by 12 publications

References 45 publications

Mutational landscape of B‐cell post‐transplant lymphoproliferative disorders

Mutational landscape of B‐cell post‐transplant lymphoproliferative disorders

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in post‐transplant lymphoproliferative disorders: association with Epstein–Barr virus, PD‐L1 copy number alterations, and outcome

Clinical and Pathological Review of Post Transplant Lymphoproliferative Disorders

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