Cell‐of‐origin classification by gene expression and <i>MYC</i>‐rearrangements in diffuse large B‐cell lymphoma of children and adolescents

Lange, J.; Köhler, Christian; Masqué-Soler, Neus; Zimmermann, Martin; Aukema, Sietse M.; Altenbuchinger, Michael; Rehberg, Thorsten; Mahn, F.; Siebert, Reiner; Spang, Rainer; Burkhardt, Birgit; Klapper, Wolfram

doi:10.1111/bjh.14812

Cited by 24 publications

(17 citation statements)

References 13 publications

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“…Two patients in the BL/DLBCL/HGBCL cohort overlapped with our recent publication on the mutational landscape of mnBLL,11q, 6 and one patient in the FL/DLBCL cohort overlapped with our previous publication on paediatric DLBCL 7 . The two cohorts do not otherwise overlap with our previous publications on the initial description of LBCL‐ IRF4 and mnBLL,11q 2,3 …”

Section: Methodsmentioning

confidence: 54%

Experience with provisional WHO‐entities large B‐cell lymphoma with IRF4‐rearrangement and Burkitt‐like lymphoma with 11q aberration in paediatric patients of the NHL‐BFM group

et al. 2020

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Summary Large B‐cell lymphoma with IRF4 rearrangement, and Burkitt‐like lymphoma with 11q aberration are two provisional lymphoma entities in the 2017 revision of the WHO classification of lymphoid neoplasms. Despite being more frequent in young patients, knowledge regarding their true incidence and clinical features in unselected cohorts of paediatric and adolescent patients is limited. We screened for both entities among paediatric patients (<18 years of age) in the German NHL‐BFM (Non‐Hodgkin lymphoma Berlin‐Frankfurt‐Münster) group. Among follicular lymphomas and diffuse large B‐cell lymphomas (DLBCL), 7/34 cases (21%) showed an IRF4 break‐apart pattern by fluorescence in situ hybridisation (FISH) and are associated with stages I and II disease (P = 0·043). Among lymphomas morphologically resembling Burkitt lymphoma, DLBCL and high‐grade B‐cell lymphoma, unclassifiable, 13/102 cases (13%) lacked a MYC break‐apart pattern but were positive for 11q proximal gain and telomeric loss by FISH. MYC‐negative Burkitt‐like lymphomas with the typical 11q gain‐loss pattern by FISH were older (P = 0·004), showed less male predominance (P = 0·003), lower stage (P = 0·040), lower serum LDH level (P = 0·01) and less abdominal involvement (P = 0·008) compared to high grade B‐cell lymphomas without 11q gain‐loss pattern. Both entities showed excellent outcome with overall survival of 100% when managed according to NHL‐BFM strategies and may provide candidates for future therapy de‐escalation in clinical trials.

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Section: Methodsmentioning

confidence: 54%

Experience with provisional WHO‐entities large B‐cell lymphoma with IRF4‐rearrangement and Burkitt‐like lymphoma with 11q aberration in paediatric patients of the NHL‐BFM group

et al. 2020

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“…The training cohort comprised 42 FFPE tissue sections, that represented 18 ABC, 4 unclassified, and 20 GBC DLBCL cases based on COO subtyping by the Affymetrix GeneChip technology (gold standard of classification) 20 . For the two validation cohorts, which comprised 42 and 31 DLBCL cases, respectively, COO classification had been accomplished by NanoString nCounter gene-expression profiling using the most recent version of the Regensburg classifier 7 , with feature weights and thresholds given in Szczepanowski et al 21 . The second validation cohort (n = 31) included only DLBCL cases aged >75 years at the time of diagnosis.…”

Section: Specimens and Methodsmentioning

confidence: 99%

“…For classification of DLBCLs into their COO subtypes, we trained a penalized linear regression model on the 780 protein groups of the training set that had been also successfully quantitated in the first validation set. For this purpose, we performed zero-sum elastic net regression 18,19 , with GCB scores provided by the MMML consortium 21 , as the continuous response variable and protein intensities as predictor variables. Since zero-sum regression does not require any prior normalization steps, we used the raw, log 2 -transformed protein group intensities as predictor variables.…”

Section: Proteome Analysis By Microlc-ms/ms On An Ab Sciex Tripletof mentioning

confidence: 99%

Platform independent protein-based cell-of-origin subtyping of diffuse large B-cell lymphoma in formalin-fixed paraffin-embedded tissue

Reinders

Altenbuchinger

Limm

et al. 2020

Sci Rep

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Diffuse large B-cell lymphoma (DLBCL) is commonly classified by gene expression profiling according to its cell of origin (COO) into activated B-cell (ABC)-like and germinal center B-cell (GCB)-like subgroups. Here we report the application of label-free nano-liquid chromatography-Sequential Window Acquisition of all THeoretical fragment-ion spectra-mass spectrometry (nanoLC-SWATH-MS) to the COO classification of DLBCL in formalin-fixed paraffin-embedded (FFPE) tissue. To generate a protein signature capable of predicting Affymetrix-based GCB scores, the summed log 2-transformed fragment ion intensities of 780 proteins quantified in a training set of 42 DLBCL cases were used as independent variables in a penalized zero-sum elastic net regression model with variable selection. The eight-protein signature obtained showed an excellent correlation (r = 0.873) between predicted and true GCB scores and yielded only 9 (21.4%) minor discrepancies between the three classifications: ABC, GCB, and unclassified. The robustness of the model was validated successfully in two independent cohorts of 42 and 31 DLBCL cases, the latter cohort comprising only patients aged >75 years, with Pearson correlation coefficients of 0.846 and 0.815, respectively, between predicted and NanoString nCounter based GCB scores. We further show that the 8-protein signature is directly transferable to both a triple quadrupole and a Q Exactive quadrupole-Orbitrap mass spectrometer, thus obviating the need for proprietary instrumentation and reagents. This method may therefore be used for robust and competitive classification of DLBCLs on the protein level. Diffuse large B-cell lymphoma (DLBCLs) is commonly grouped into three distinct molecular subtypes based on the putative cell of origin (COO): the activated B-cell-like (ABC), the germinal B-cell-like (GCB), and the unclassifiable subtype as defined by array-based gene expression profiling 1. Numerous studies have confirmed the distinct differences in biology and clinical behavior of these subtypes and, therefore, determination of COO has become an integral component in the diagnosis of DLBCL, providing a basis for targeted-treatment stratification 2. GCB-like DLBCL has shown consistently better response to treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) without and with the addition of rituximab (R-CHOP). However, the requirement for high quality tumor RNA from snap frozen DLBCL biopsies represented a significant obstacle to

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“…the Lymph2Cx assay from NanoString Technologies, Seattle, WA, USA) can identify DLBCL molecular subtypes [30]. Moreover, those methods are characterised by high compliance level with GEP microarrays and satisfactory reproducibility between laboratories [30,31,32]. Possibly, tests based on GEP will be a more precise diagnostic method than currently approved by the WHO IHC methods in future [1,20].…”

Section: Fig 1 Ebv Detection: A) Immunohistochemical Staining With mentioning

confidence: 99%

Comprehensive histopathological diagnostics of aggressive B-cell lymphomas based on the updated criteria of the World Health Organisation’s 2017 classification

Szumera‐Ciećkiewicz¹,

Rymkiewicz²,

Grygalewicz³

et al. 2018

pjp

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Revision of the fourth edition of the World Health Organisation (WHO) Classification of Haematopoietic and Lymphatic Tissues, which was published in 2017, introduced important changes updating the biology, pathology, genetics, and clinical presentation of aggressive B-cell lymphomas. High grade B-cell lymphomas (HG-BLs) replaced B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, the new provisional entityBurkitt-like lymphoma with 11q aberration was identified, and some categories were upgraded, e.g. EBV-positive diffuse large B-cell lymphoma, not otherwise specified. Still the histopathological diagnostics is based on morphology and immunoprofile, but to define the HGBLs evaluation of MYC, BCL2, and BCL6 gene statuses is required. According to the presented WHO criteria, in the comprehensive histopathological diagnostics of aggressive B-cell lymphomas a highly specialised diagnostic team including a pathologist, a molecular biologist, a geneticist, a haematologist, and immunophenotyping technicians is needed.

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Cell‐of‐origin classification by gene expression and MYC‐rearrangements in diffuse large B‐cell lymphoma of children and adolescents

Cited by 24 publications

References 13 publications

Experience with provisional WHO‐entities large B‐cell lymphoma with IRF4‐rearrangement and Burkitt‐like lymphoma with 11q aberration in paediatric patients of the NHL‐BFM group

Experience with provisional WHO‐entities large B‐cell lymphoma with IRF4‐rearrangement and Burkitt‐like lymphoma with 11q aberration in paediatric patients of the NHL‐BFM group

Platform independent protein-based cell-of-origin subtyping of diffuse large B-cell lymphoma in formalin-fixed paraffin-embedded tissue

Comprehensive histopathological diagnostics of aggressive B-cell lymphomas based on the updated criteria of the World Health Organisation’s 2017 classification

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