TY - JOUR A1 - Ritter, Julia A1 - Zimmermann, Karin A1 - Jöhrens, Korinna A1 - Mende, Stefanie A1 - Seegebarth, Anke A1 - Siegmund, Britta A1 - Hennig, Steffen A1 - Todorova, Kremena A1 - Rosenwald, Andreas A1 - Daum, Severin A1 - Hummel, Michael A1 - Schumann, Michael T1 - T-cell repertoires in refractory coeliac disease JF - Gut N2 - Objective Refractory coeliac disease (RCD) is a potentially hazardous complication of coeliac disease (CD). In contrast to RCD type I, RCD type II is a precursor entity of enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL. Using high-throughput sequencing (HTS), we aimed to establish the small-intestinal T-cell repertoire (TCR) in CD and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis. Design DNA extracted from duodenal mucosa specimens of controls (n=9), active coeliacs (n=10), coeliacs on a gluten-free diet (n=9), RCD type I (n= 8), RCD type II (n= 8) and unclassified Marsh I cases (n= 3) collected from 2002 to 2013 was examined by TCR beta-complementarity- determining regions 3 (CDR3) multiplex PCR followed by HTS of the amplicons. Results On average, 106 sequence reads per sample were generated consisting of up to 900 individual TCR beta rearrangements. In RCD type II, the most frequent clonotypes (ie, sequence reads with identical CDR3) represent in average 42.6% of all TCR beta rearrangements, which was significantly higher than in controls (6.8%; p<0.01) or RCD type I (6.7%; p<0.01). Repeat endoscopies in individual patients revealed stability of clonotypes for up to several years without clinical symptoms of EATL. Dominant clonotypes identified in individual patients with RCD type II were unique and not related between patients. CD-associated, gliad-independent CDR3 motifs were only detectable at low frequencies. Conclusions TCR beta-HTS analysis unravels the TCR in CD and allows detailed analysis of individual TCR beta rearrangements. Dominant TCR beta sequences identified in patients with RCD type II are unique and not homologous to known gliadin-specific TCR sequences, supporting the assumption that these clonal T-cells expand independent of gluten stimulation. KW - Intestinal Intraepithelial Lymphocy KW - Delta Repertoire KW - Lymphoma KW - Usage KW - Clonality KW - Sprue KW - Chains KW - Design KW - Epitope KW - Frequency Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226350 VL - 67 IS - 4 ER - TY - JOUR A1 - Aukema, Sietse M. A1 - Kreuz, Markus A1 - Kohler, Christian W. A1 - Rosolowski, Maciej A1 - Hasenclever, Dirk A1 - Hummel, Michael A1 - Küppers, Ralf A1 - Lenze, Diddo A1 - Ott, German A1 - Pott, Christiane A1 - Richter, Julia A1 - Rosenwald, Andreas A1 - Szczepanowski, Monika A1 - Schwaenen, Carsten A1 - Stein, Harald A1 - Trautmann, Heiko A1 - Wessendorf, Swen A1 - Trümper, Lorenz A1 - Loeffler, Markus A1 - Spang, Rainer A1 - Kluin, Philip M. A1 - Klapper, Wolfram A1 - Siebert, Reiner T1 - Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma JF - Haematologica N2 - Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC+ lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC+-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC+ and BCL2(+)/MYC+ double-hit lymphomas. BCL2(+)/MYC+ double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC+ lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC+ lymphomas sharing various molecular characteristics. KW - Rituximab plus KW - cyclophsophamide KW - c-myc KW - gene expression KW - genomic aberrations KW - follicular lymphoma KW - prognostic factor KW - poor prognosis KW - grade 3B KW - distinct Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116882 SN - 1592-8721 VL - 99 IS - 4 ER - 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 - Kist, Markus A1 - Thomaschewski, Michael A1 - Keck, Yannick A1 - Abdalla, Thaer S. A. A1 - Zeissig, Sylke Ruth A1 - Kleihues-van Tol, Kees A1 - Wellner, Ulrich Friedrich A1 - Keck, Tobias A1 - Hoeppner, Jens A1 - Hummel, Richard T1 - Specifics of young gastric cancer patients: a population-based analysis of 46,110 patients with gastric cancer from the German Clinical Cancer Registry Group JF - Cancers N2 - Introduction: 2–8% of all gastric cancer occurs at a younger age, also known as early-onset gastric cancer (EOGC). The aim of the present work was to use clinical registry data to classify and characterize the young cohort of patients with gastric cancer more precisely. Methods: German Cancer Registry Group of the Society of German Tumor Centers—Network for Care, Quality and Research in Oncology (ADT)was queried for patients with gastric cancer from 2000–2016. An approach that stratified relative distributions of histological subtypes of gastric adenocarcinoma according to age percentiles was used to define and characterize EOGC. Demographics, tumor characteristics, treatment and survival were analyzed. Results: A total of 46,110 patients were included. Comparison of different groups of age with incidences of histological subtypes showed that incidence of signet ring cell carcinoma (SRCC) increased with decreasing age and exceeded pooled incidences of diffuse and intestinal type tumors in the youngest 20% of patients. We selected this group with median age of 53 as EOGC. The proportion of female patients was lower in EOGC than that of elderly patients (43% versus 45%; p < 0.001). EOGC presented more advanced and undifferentiated tumors with G3/4 stages in 77% versus 62%, T3/4 stages in 51% versus 48%, nodal positive tumors in 57% versus 53% and metastasis in 35% versus 30% (p < 0.001) and received less curative treatment (42% versus 52%; p < 0.001). Survival of EOGC was significantly better (five-years survival: 44% versus 31% (p < 0.0001), with age as independent predictor of better survival (HR 0.61; p < 0.0001). Conclusion: With this population-based registry study we were able to objectively define a cohort of patients referred to as EOGC. Despite more aggressive/advanced tumors and less curative treatment, survival was significantly better compared to elderly patients, and age was identified as an independent predictor for better survival. KW - gastric cancer in young patients KW - german clinical cancer registry group KW - early-onset gastric cancer patients Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297473 SN - 2072-6694 VL - 14 IS - 23 ER -