TY - JOUR A1 - Loeffler-Wirth, Henry A1 - Kreuz, Markus A1 - Hopp, Lydia A1 - Arakelyan, Arsen A1 - Haake, Andrea A1 - Cogliatti, Sergio B. A1 - Feller, Alfred C. A1 - Hansmann, Martin-Leo A1 - Lenze, Dido A1 - Möller, Peter A1 - Müller-Hermelink, Hans Konrad A1 - Fortenbacher, Erik A1 - Willscher, Edith A1 - Ott, German A1 - Rosenwald, Andreas A1 - Pott, Christiane A1 - Schwaenen, Carsten A1 - Trautmann, Heiko A1 - Wessendorf, Swen A1 - Stein, Harald A1 - Szczepanowski, Monika A1 - Trümper, Lorenz A1 - Hummel, Michael A1 - Klapper, Wolfram A1 - Siebert, Reiner A1 - Loeffler, Markus A1 - Binder, Hans T1 - A modular transcriptome map of mature B cell lymphomas JF - Genome Medicine N2 - Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. KW - tumor heterogeneity KW - B cell malignancies KW - gene regulation KW - molecular subtypes KW - machine learning Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237262 VL - 11 ER - TY - JOUR A1 - Schümann, Franziska Lea A1 - Groß, Elisabeth A1 - Bauer, Marcus A1 - Rohde, Christian A1 - Sandmann, Sarah A1 - Terziev, Denis A1 - Müller, Lutz P. A1 - Posern, Guido A1 - Wienke, Andreas A1 - Fend, Falko A1 - Hansmann, Martin-Leo A1 - Klapper, Wolfram A1 - Rosenwald, Andreas A1 - Stein, Harald A1 - Dugas, Martin A1 - Müller-Tidow, Carsten A1 - Wickenhauser, Claudia A1 - Binder, Mascha A1 - Weber, Thomas T1 - Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas JF - Biomedicines N2 - T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95% confidence interval (CI): 0.044–0.767; p = 0.020;) and EZH2 (HR = 8.245; 95% CI: 1.898–35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients. KW - T-cell non-Hodgkin's lymphomas KW - PTCL KW - epigenetics KW - EZH1 KW - EZH2 KW - H3K27me3 KW - immunohistochemistry KW - next generation sequencing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252155 SN - 2227-9059 VL - 9 IS - 12 ER - TY - JOUR A1 - Richter, Julia A1 - Hüttmann, Andreas A1 - Rekowski, Jan A1 - Schmitz, Christine A1 - Gärtner, Selina A1 - Rosenwald, Andreas A1 - Hansmann, Martin-Leo A1 - Hartmann, Sylvia A1 - Möller, Peter A1 - Wacker, Hans-Heinrich A1 - Feller, Alfred A1 - Thorns, Christoph A1 - Müller, Stefan A1 - Dührsen, Ulrich A1 - Klapper, Wolfram T1 - Molecular characteristics of diffuse large B-cell lymphoma in the Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin lymphomas (PETAL) trial: correlation with interim PET and outcome JF - Blood Cancer Journal N2 - No abstract available KW - Cancer genetics KW - Medical research KW - Translational research Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226185 VL - 9 ER - TY - JOUR A1 - Hartmann, Sylvia A1 - Plütschow, Annette A1 - Mottok, Anja A1 - Bernd, Heinz‐Wolfram A1 - Feller, Alfred C. A1 - Ott, German A1 - Cogliatti, Sergio A1 - Fend, Falko A1 - Quintanilla‐Martinez, Leticia A1 - Stein, Harald A1 - Klapper, Wolfram A1 - Möller, Peter A1 - Rosenwald, Andreas A1 - Engert, Andreas A1 - Hansmann, Martin‐Leo A1 - Eichenauer, Dennis A. T1 - The time to relapse correlates with the histopathological growth pattern in nodular lymphocyte predominant Hodgkin lymphoma JF - American Journal of Hematology N2 - Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first‐line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse. KW - Hodgkin lymphoma KW - relapse KW - growth patterns Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212594 VL - 94 IS - 11 SP - 1208 EP - 1213 ER -