Distinct subtypes of post-transplant lymphoproliferative disorders: CHIP-like mutations in early lesions and substantial mutational differences between EBV-positive and EBV-negative diffuse large B-cell lymphomas

Vanesa-Sindi Ivanova; Thomas Menter; Ningxuan Cui; Peter Leary; Carl Zinner; Jörg P Halter; Frank Stenner; Stefan Dirnhofer; Anne Müller; Alexandar Tzankov

doi:10.1111/bjh.19952

Distinct subtypes of post-transplant lymphoproliferative disorders: CHIP-like mutations in early lesions and substantial mutational differences between EBV-positive and EBV-negative diffuse large B-cell lymphomas

Br J Haematol. 2025 Jan 7. doi: 10.1111/bjh.19952. Online ahead of print.

Authors

Affiliations

¹ Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
² Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
³ Haematology, University Hospital Basel, Basel, Switzerland.
⁴ Oncology, University Hospital Basel, Basel, Switzerland.

PMID: 39777628
DOI: 10.1111/bjh.19952

Abstract

Post-transplant lymphoproliferative disorders (PTLD) and lymphomas in immunocompromised individuals represent significant clinical challenges, with a limited understanding of their pathogenesis. We investigated a PTLD cohort (n = 50) consisting of 'early lesions' (infectious mononucleosis-like PTLD, plasmacytic and follicular hyperplasias), polymorphic PTLD and post-transplant diffuse large B-cell lymphomas (PT-DLBCL). The study also included 15 DLBCL with autoimmune/immunocompromised backgrounds (IS-DLBCL) and 14 DLBCL, not otherwise specified (DLBCL, NOS), as control. To investigate microarchitectural and genetic changes, immunohistochemistry, multiplex immunofluorescence (mIF), fluorescence in situ hybridisation and high-throughput sequencing were performed. Scarcity of viral infections other than Epstein-Barr virus (EBV) was observed. mIF revealed lower Treg infiltration in PT-DLBCL and high CD8⁺/PD1⁺ T cells in IS-DLBCL. MYC rearrangements were most common in PT-DLBCL, followed by IS-DLBCL and DLBCL, NOS, all EBV-negative. TP53 mutations were frequent in EBV-negative PT-DLBCL and DLBCL, NOS but absent in 'early lesions'. NOTCH1 mutations were predominant in PT-DLBCL (N1 DLBCL-subgroup). Gene expression profiling showed a significant overlap between 'early lesions' and polymorphic PTLD. The presence of clonal haematopoiesis of indeterminate potential (CHIP)-like mutations and the absence of immune-escape gene mutations in 'early lesions' suggest these disorders may represent clonal expansions driven by exogenic immunosuppression and/or EBV infection 'substituting' for mutations of the latter group of genes.

Keywords: diffuse large B‐cell lymphomas (DLBCL); gene expression profiling (GEP); high‐throughput sequencing (HTS); immunosuppression; post‐transplant lymphoproliferative disease (PTLD).

Grants and funding

KFS-5228-02-2021/Krebsliga Schweiz