Array CGH-based analysis of post-transplant plasmacytic hyperplasia reveals ‘intact genomes’ arguing against categorizing it as part of the post-transplant lymphoproliferative disease spectrum

Menter, Thomas; Juškevičius, Darius; Tzankov, Alexandar

doi:10.1111/tri.12400

Cited by 3 publications

(2 citation statements)

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“…Black arrows show nuclei of non-neoplastic lymphocytes representing unwanted contamination of the enrichment. Small non-neoplastic cell nuclei were negative for the investigated markers confirming the specificity of the stainings [27,46,49]. Major obstacles to be overcome are preservation of tissue antigenicity and development of a bright and specific signal, which enables recognition of marker expression in cytometry analysis.…”

Section: Discussionmentioning

confidence: 64%

Novel cell enrichment technique for robust genetic analysis of archival classical Hodgkin lymphoma tissues

Juškevičius

Jucker

Dietsche

et al. 2018

Laboratory Investigation

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Approximately 15% of patients with classical Hodgkin lymphoma (cHL) die after relapse or progressive disease. Comprehensive genetic characterization is required to better understand its molecular pathology and improve management. However, genetic information on cHL is hard to obtain mainly due to rare malignant Hodgkin- and Reed-Sternberg cells (HRSC), whose overall frequencies in the affected tissues ranges from 0.1 to 10%. Therefore, enrichment of neoplastic cells is necessary for the majority of genetic investigations. We have developed a new high-throughput method for marker-based enrichment of archival formalin-fixed and paraffin-embedded (FFPE) tissue-derived HRSC nuclei by fluorescence-assisted flow sorting (FACS) and successfully applied it on ten cHL cases. Genomic DNA extracted from sorted nuclei was used for targeted high-throughput sequencing (HTS) of 68 genes that are frequently affected in lymphomas. Chromosomal copy number aberrations were investigated by the Agilent SurePrint 180k microarray. Our method enabled HRSC nuclei enrichment to 40-90% in sorted populations. This level of enrichment was sufficient for reliable identification of tumor-specific mutations and copy number aberrations. Genetic analysis revealed that components of JAK-STAT signaling pathway were affected in all investigated tumors by frequent mutations of SOCS1 and STAT6 as well as copy number gains of JAK2. Involvement of nuclear factor-κB (NF-κB) pathway compounds was evident from recurrent gains of the locus containing the REL gene and mutations in TNFAIP3 and CARD11. Finally, genetic alterations of PD-L1 and B2M suggested immune evasion as mechanisms of oncogenesis in some patients. In this work, we present a new method for HRSC enrichment from FFPE tissue blocks by FACS and demonstrate the feasibility of a wide-scale genetic analysis by cutting-edge molecular methods. Our work opens the door to a large resource of archived clinical cHL samples and lays foundation to more complex studies aimed to answer important biological and clinical questions that are critical to improve cHL management.

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Section: Discussionmentioning

confidence: 64%

Novel cell enrichment technique for robust genetic analysis of archival classical Hodgkin lymphoma tissues

Juškevičius

Jucker

Dietsche

et al. 2018

Laboratory Investigation

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“…Altogether, 22 patients could be enclosed in this study. Five patients with early forms of PTLD were analysed in a separate study . Patients' characteristics are summarized in Table .…”

Section: Methodsmentioning

confidence: 99%

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

Menter

Dickenmann

Juškevičius

et al. 2016

Hematological Oncology

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Post-transplant lymphoproliferative disorders (PTLD) are a major problem in transplant medicine. So far, the insights into pathogenesis and potentially druggable pathways in PTLD remain scarce. We investigated a cohort of PTLD patients, consisting of both polymorphic (n = 3) and monomorphic (n = 19) B-cell lymphoproliferations. Several signalling pathways, cell of origin of PTLD and their relation to viruses were analysed by immunohistochemistry and in situ hybridization. Most PTLD were of activated B-cell origin. Two-thirds of cases showed an Epstein-Barr virus (EBV) infection of the neoplastic cells. NF-κB signalling components were present in the majority of cases, except for EBV-infected cases with latency type III lacking CD19 and upstream B-cell signalling constituents. Proteins involved in B-cell receptor signalling like Bruton tyrosine kinase were only present in a minority of cases. Phosphoinositide 3-kinase (PI3K) was expressed in 94% of cases and the druggable PI3K class 1 catalytic subunit p110 in 76%, while proteins of other signalling transduction pathways were expressed only in single cases. Unsupervised cluster analysis revealed three distinct subgroups: (i) related to EBV infection, mainly latency type III and mostly lacking CD19, upstream B-cell signalling and NF-κB constituents; (ii) mostly related to EBV infection with expression of the alternative NF-κB pathway compound RelB, CD10, and FOXP1 or MUM1; and finally, (iii) mostly unrelated to virus infection with expression of the classic NF-κB pathway compound p65. EBV and NF-κB are important drivers in PTLD in contrast to B-cell receptor signalling. The main signal transduction pathway is related to PI3K. This links PTLD to other subgroups of EBV-related lymphomas, highlighting also new potential treatment approaches. Copyright © 2016 John Wiley & Sons, Ltd.

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Hematopathology

Piña‐Oviedo¹,

Khogeer²,

Tang³

et al. 2020

Oncological Surgical Pathology

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Array CGH-based analysis of post-transplant plasmacytic hyperplasia reveals ‘intact genomes’ arguing against categorizing it as part of the post-transplant lymphoproliferative disease spectrum

Cited by 3 publications

References 6 publications

Novel cell enrichment technique for robust genetic analysis of archival classical Hodgkin lymphoma tissues

Novel cell enrichment technique for robust genetic analysis of archival classical Hodgkin lymphoma tissues

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

Hematopathology

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