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3. Transcriptional reprogramming by mutated IRF4 in lymphoma

Author

Schleussner, Nikolai, Cauchy, Pierre, Franke, Vedran, Giefing, Maciej, Fornes, Oriol, Vankadari, Naveen, Assi, Salam A., Costanza, Mariantonia, Weniger, Marc A., Akalin, Altuna, Anagnostopoulos, Ioannis, Bukur, Thomas, Casarotto, Marco G., Damm, Frederik, Daumke, Oliver, Edginton-White, Benjamin, Gebhardt, J. Christof M., Grau, Michael, Grunwald, Stephan, Hansmann, Martin-Leo, Hartmann, Sylvia, Huber, Lionel, Kärgel, Eva, Lusatis, Simone, Noerenberg, Daniel, Obier, Nadine, Pannicke, Ulrich, Fischer, Anja, Reisser, Anja, Rosenwald, Andreas, Schwarz, Klaus, Sundararaj, Srinivasan, Weilemann, Andre, Winkler, Wiebke, Xu, Wendan, Lenz, Georg, Rajewsky, Klaus, Wasserman, Wyeth W., Cockerill, Peter N., Scheidereit, Claus, Siebert, Reiner, Küppers, Ralf, Grosschedl, Rudolf, Janz, Martin, Bonifer, Constanze, and Mathas, Stephan

Published
2023
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4. Publisher Correction: Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker

Author

Johansson, Patricia, Laguna, Teresa, Ossowski, Julio, Pancaldi, Vera, Brauser, Martina, Dührsen, Ulrich, Keuneke, Lara, Queiros, Ana, Richter, Julia, Martín-Subero, José I., Siebert, Reiner, Schlegelberger, Brigitte, Küppers, Ralf, Dürig, Jan, Penas, Eva M. Murga, Pau, Enrique Carrillo-de Santa, and Bergmann, Anke K.

Published
2023
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5. The genomic and transcriptional landscape of primary central nervous system lymphoma

Author

Radke, Josefine, Ishaque, Naveed, Koll, Randi, Gu, Zuguang, Schumann, Elisa, Sieverling, Lina, Uhrig, Sebastian, Hübschmann, Daniel, Toprak, Umut H., López, Cristina, Hostench, Xavier Pastor, Borgoni, Simone, Juraeva, Dilafruz, Pritsch, Fabienne, Paramasivam, Nagarajan, Balasubramanian, Gnana Prakash, Schlesner, Matthias, Sahay, Shashwat, Weniger, Marc, Pehl, Debora, Radbruch, Helena, Osterloh, Anja, Korfel, Agnieszka, Misch, Martin, Onken, Julia, Faust, Katharina, Vajkoczy, Peter, Moskopp, Dag, Wang, Yawen, Jödicke, Andreas, Trümper, Lorenz, Anagnostopoulos, Ioannis, Lenze, Dido, Küppers, Ralf, Hummel, Michael, Schmitt, Clemens A., Wiestler, Otmar D., Wolf, Stephan, Unterberg, Andreas, Eils, Roland, Herold-Mende, Christel, Brors, Benedikt, Siebert, Reiner, Wiemann, Stefan, and Heppner, Frank L.

Published
2022
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7. Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas

Author

Hübschmann, Daniel, Kleinheinz, Kortine, Wagener, Rabea, Bernhart, Stephan H., López, Cristina, Toprak, Umut H., Sungalee, Stephanie, Ishaque, Naveed, Kretzmer, Helene, Kreuz, Markus, Waszak, Sebastian M., Paramasivam, Nagarajan, Ammerpohl, Ole, Aukema, Sietse M., Beekman, Renée, Bergmann, Anke K., Bieg, Matthias, Binder, Hans, Borkhardt, Arndt, Borst, Christoph, Brors, Benedikt, Bruns, Philipp, Carrillo de Santa Pau, Enrique, Claviez, Alexander, Doose, Gero, Haake, Andrea, Karsch, Dennis, Haas, Siegfried, Hansmann, Martin-Leo, Hoell, Jessica I., Hovestadt, Volker, Huang, Bingding, Hummel, Michael, Jäger-Schmidt, Christina, Kerssemakers, Jules N. A., Korbel, Jan O., Kube, Dieter, Lawerenz, Chris, Lenze, Dido, Martens, Joost H. A., Ott, German, Radlwimmer, Bernhard, Reisinger, Eva, Richter, Julia, Rico, Daniel, Rosenstiel, Philip, Rosenwald, Andreas, Schillhabel, Markus, Stilgenbauer, Stephan, Stadler, Peter F., Martín-Subero, José I., Szczepanowski, Monika, Warsow, Gregor, Weniger, Marc A., Zapatka, Marc, Valencia, Alfonso, Stunnenberg, Hendrik G., Lichter, Peter, Möller, Peter, Loeffler, Markus, Eils, Roland, Klapper, Wolfram, Hoffmann, Steve, Trümper, Lorenz, Küppers, Ralf, Schlesner, Matthias, and Siebert, Reiner

Published
2021
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10. Lymphocyte predominant cells detect Moraxella catarrhalis-derived antigens in nodular lymphocyte-predominant Hodgkin lymphoma

Author

Thurner, Lorenz, Hartmann, Sylvia, Fadle, Natalie, Regitz, Evi, Kemele, Maria, Kim, Yoo-Jin, Bohle, Rainer Maria, Nimmesgern, Anna, von Müller, Lutz, Kempf, Volkhard A. J., Weniger, Marc A., Neumann, Frank, Schneider, Nadine, Vornanen, Martine, Sundström, Christer, de Leval, Laurence, Engert, Andreas, Eichenauer, Dennis A., Küppers, Ralf, Preuss, Klaus-Dieter, Hansmann, Martin-Leo, and Pfreundschuh, Michael

Published
2020
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11. Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

Author

Wierzbinska, Justyna A., Toth, Reka, Ishaque, Naveed, Rippe, Karsten, Mallm, Jan-Philipp, Klett, Lara C., Mertens, Daniel, Zenz, Thorsten, Hielscher, Thomas, Seifert, Marc, Küppers, Ralf, Assenov, Yassen, Lutsik, Pavlo, Stilgenbauer, Stephan, Roessner, Philipp M., Seiffert, Martina, Byrd, John, Oakes, Christopher C., Plass, Christoph, and Lipka, Daniel B.

Published
2020
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13. Human IgM–expressing memory B cells.

Author

Budeus, Bettina, Kibler, Artur, and Küppers, Ralf

Subjects
IMMUNOLOGIC memory, B cells, ANTIGEN receptors, GERMINAL centers, T cells
Abstract

A hallmark of T cell dependent (TD) humoral immune responses is the generation of long–lived memory B cells. The generation of these cells occurs primarily in the germinal center (GC) reaction, where antigen–activated B cells undergo affinity maturation as a major consequence of the combined processes of proliferation, somatic hypermutation of their immunoglobulin V (IgV) region genes, and selection for improved affinity of their B–cell antigen receptors. As many B cells also undergo class–switching to IgG or IgA in these TD responses, there was traditionally a focus on class–switched memory B cells in both murine and human studies on memory B cells. However, it has become clear that there is also a large subset of IgM–expressing memory B cells, which have important phenotypic and functional similarities but also differences to class–switched memory B cells. There is an ongoing discussion about the origin of distinct subsets of human IgM+ B cells with somatically mutated IgV genes. We argue here that the vast majority of human IgM–expressing B cells with somatically mutated IgV genes in adults is indeed derived from GC reactions, even though a generation of some mostly lowly mutated IgM+ B cells from other differentiation pathways, mainly in early life, may exist. [ABSTRACT FROM AUTHOR]

Published
2023
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17. Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Author

López, Cristina, Kleinheinz, Kortine, Aukema, Sietse M., Rohde, Marius, Bernhart, Stephan H., Hübschmann, Daniel, Wagener, Rabea, Toprak, Umut H., Raimondi, Francesco, Kreuz, Markus, Waszak, Sebastian M., Huang, Zhiqin, Sieverling, Lina, Paramasivam, Nagarajan, Seufert, Julian, Sungalee, Stephanie, Russell, Robert B., Bausinger, Julia, Kretzmer, Helene, Ammerpohl, Ole, Bergmann, Anke K., Binder, Hans, Borkhardt, Arndt, Brors, Benedikt, Claviez, Alexander, Doose, Gero, Feuerbach, Lars, Haake, Andrea, Hansmann, Martin-Leo, Hoell, Jessica, Hummel, Michael, Korbel, Jan O., Lawerenz, Chris, Lenze, Dido, Radlwimmer, Bernhard, Richter, Julia, Rosenstiel, Philip, Rosenwald, Andreas, Schilhabel, Markus B., Stein, Harald, Stilgenbauer, Stephan, Stadler, Peter F., Szczepanowski, Monika, Weniger, Marc A., Zapatka, Marc, Eils, Roland, Lichter, Peter, Loeffler, Markus, Möller, Peter, Trümper, Lorenz, Klapper, Wolfram, ICGC MMML-Seq Consortium, Hoffmann, Steve, Küppers, Ralf, Burkhardt, Birgit, Schlesner, Matthias, and Siebert, Reiner

Published
2019
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18. Clonal composition and differentiation stage of human CD30+ B cells in reactive lymph nodes.

Author

Küppers, Ralf, Budeus, Bettina, Hartmann, Sylvia, and Hansmann, Martin-Leo

Subjects
B cells, B cell differentiation, LYMPH nodes, LYMPHADENITIS, HODGKIN'S disease
Abstract

Introduction: Normal CD30+ B cells represent a distinct B-cell differentiation stage with features of strong activation. We lack an in depth understanding of these cells, because they are not present in peripheral blood and are typically very rare in reactive lymphoid organs. CD30+ B cells have been discussed as a potential precursor population for the malignant CD30+ Hodgkin and Reed-Sternberg cells in classical Hodgkin lymphoma. As CD30+ B cells can be more numerous in some cases of reactive lymphadenitis, we aimed to characterize these CD30+ B cells in terms of their differentiation stage and clonal composition, also as a means to clarify whether such CD30+ B-cell populations may represent potential precursor lesions of Hodgkin lymphoma. Methods: We microdissected single CD30+ B cells from tissue sections of eight reactive lymph nodes with substantial numbers of such cells and sequenced their rearranged immunoglobulin (Ig) heavy chain V region (IGHV) genes. Results: The CD30+ B cells were polyclonal B cells in all instances, and they not only encompass post-germinal center (GC) B cells with mutated IGHV genes, but also include a substantial fraction of pre-germinal center B cells with unmutated IGHV genes. In five of the lymph nodes, mostly small clonal expansions were detected among the CD30+ B cells. Most of the expanded clones carried somatically mutated IGHV genes and about half of the mutated clones showed intraclonal diversity. Discussion: We conclude that in human reactive lymph nodes with relatively many CD30+ B cells, these cells are a heterogenous population of polyclonal B cells encompassing activated pre-GC B cells as well as GC and post-GC B cells, with some clonal expansions. Because of their polyclonality and frequent pre-GC differentiation stage, there is no indication that such cell-rich CD30+ B-cell populations represent precursor lesions of Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

Published
2023
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20. Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas

Author

López, Cristina, Schleussner, Nikolai, Bernhart, Stephan H., Kleinheinz, Kortine, Sungalee, Stephanie, Sczakiel, Henrike L., Kretzmer, Helene, Toprak, Umut H., Glaser, Selina, Wagener, Rabea, Ammerpohl, Ole, Bens, Susanne, Giefing, Maciej, González Sánchez, Juan C., Apic, Gordana, Hübschmann, Daniel, Janz, Martin, Kreuz, Markus, Mottok, Anja, Müller, Judith M., Seufert, Julian, Hoffmann, Steve, Korbel, Jan O., Russell, Robert B., Schüle, Roland, Trümper, Lorenz, Klapper, Wolfram, Radlwimmer, Bernhard, Lichter, Peter, Küppers, Ralf, Schlesner, Matthias, Mathas, Stephan, Siebert, Reiner, Sanchez, Juan C. Gonzalez, European Union (EU), and Horizon 2020

Subjects
Cancer Research, GENES, LANDSCAPE, MUTATIONS, BURKITT, PATHOGENESIS, Medizin, EXOME, Hematology, ddc:610, Histone methyltransferases, DDC 610 / Medicine & health
Abstract

Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas., publishedVersion

Published
2023

21. Expression profile of translation initiation factor eIF2B5 in diffuse large B-cell lymphoma and its correlation to clinical outcome

Author

Unterluggauer, Julia J., Prochazka, Katharina, Tomazic, Peter V., Huber, Heinrich J., Seeboeck, Rita, Fechter, Karoline, Steinbauer, Elisabeth, Gruber, Verena, Feichtinger, Julia, Pichler, Martin, Weniger, Marc A., Küppers, Ralf, Sill, Heinz, Schicho, Rudolf, Neumeister, Peter, Beham-Schmid, Christine, Deutsch, Alexander J. A., and Haybaeck, Johannes

Published
2018
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23. NFDI4Immuno - Letter of Intent

Author

Busse, Christian E., Babel, Nina, Chang, Hyun-Dong, Dorhoi, Anca, Eugster, Anne, Hummel, Michael, Kammerer, Robert, Küppers, Ralf, Meyer-Hermann, Michael, Nahnsen, Sven, Schetelig, Johannes, Schwab, Nicholas, Bröker, Barbara, Eckert, Cornelia, Imkeller, Katharina, Meissner, Felix, Siewert, Katherina, and Zehn, Dietmar

Subjects
NFDI, AIRR, FOS: Clinical medicine, Immunology
Abstract

Binding Letter of Intent of the NFDI4Immuno consortium initiative for the German National Research Data Infrastructure (NFDI) Program.

Published
2021
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26. NGS-Based High-Throughput Screen to Identify MicroRNAs Regulating Growth of B-Cell Lymphoma

Author

Kluiver, Joost, Niu, Fubiao, Yuan, Ye, Kok, Klaas, van den Berg, Anke, Dzikiewicz-Krawczyk, Agnieszka, Küppers, Ralf, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), and Translational Immunology Groningen (TRIGR)

Subjects
0301 basic medicine, Cell growth, Library preparation, Computational biology, Biology, medicine.disease, 3. Good health, Lymphoma, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, microRNA, medicine, Protein translation, B-cell lymphoma
Abstract

MicroRNAs (miRNAs) play important roles in development, differentiation, and homeostasis by regulating protein translation. In B-cell lymphoma, many miRNAs have altered expression levels, and for a limited subset of them, experimental data supports their functional relevance in lymphoma pathogenesis. This chapter describes an unbiased next-generation sequencing (NGS)-based high-throughput screening approach to identify miRNAs that are involved in the control of cell growth. First, we provide a protocol for performing high-throughput screening for miRNA inhibition and overexpression. Second, we describe the procedure for next-generation sequencing library preparation. Third, we provide a workflow for data analysis.

Published
2019

33. Pathogenesis of Hodgkinʼs lymphoma

Author

Küppers, Ralf, Schmitz, Roland, Distler, Verena, Renné, Christoph, Bräuninger, Andreas, and Hansmann, Martin-Leo

Published
2014

34. Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL, Transformed Follicular Lymphoma, Richter's Trans-Formed DLBCL and Germinal Center B-Cells.

Author

Uhl, Barbara, Prochazka, Katharina T., Pansy, Katrin, Wenzl, Kerstin, Strobl, Johanna, Baumgartner, Claudia, Szmyra, Marta M., Waha, James E., Wolf, Axel, Tomazic, Peter V., Steinbauer, Elisabeth, Steinwender, Maria, Friedl, Sabine, Weniger, Marc, Küppers, Ralf, Pichler, Martin, Greinix, Hildegard T., Stary, Georg, Ramsay, Alan G., and Apollonio, Benedetta

Subjects
FOLLICULAR lymphoma, CHEMOKINE receptors, DIFFUSE large B-cell lymphomas, GERMINAL centers, BIOMARKERS, RICHTER syndrome, RITUXIMAB, OVARIAN follicle
Abstract

Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas. [ABSTRACT FROM AUTHOR]

Published
2022
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35. Loss of function mutations of BCOR in classical Hodgkin lymphoma.

Author

Giefing, Maciej, Gearhart, Micah D., Schneider, Markus, Overbeck, Birte, Klapper, Wolfram, Hartmann, Sylvia, Ustaszewski, Adam, Weniger, Marc A., Wiehle, Laura, Hansmann, Martin-Leo, Melnick, Ari, Béguelin, Wendy, Sundström, Christer, Küppers, Ralf, Bardwell, Vivian J., and Siebert, Reiner

Subjects
HODGKIN'S disease, REGULATOR genes, B cells, SOMATIC mutation, HEMATOLOGIC malignancies, GERMINAL centers
Abstract

BCOR is a component of a variant Polycomb repressive complex 1 (PRC1.1). PRC1 and PRC2 complexes together constitute a major gene regulatory system critical for appropriate cellular differentiation. The gene is upregulated in germinal center (GC) B cells and mutated in a number of hematologic malignancies. We report BCOR inactivating alterations in 4/7 classic Hodgkin lymphoma (cHL) cell lines, subclonal somatic mutations in Hodgkin and Reed–Sternberg (HRS) cells of 4/10 cHL cases, and deletions in HRS cells of 7/17 primary cHL cases. In mice, conditional loss of Bcor driven by AID-Cre in GC B cells resulted in gene expression changes of 46 genes (>2-fold) including upregulated Lef1 that encodes a transcription factor responsible for establishing T-cell identity and Il9r (interleukin-9 receptor), an important member of the cytokine network in cHL. Our findings suggest a role for BCOR loss in cHL pathogenesis and GC-B cell homeostasis. [ABSTRACT FROM AUTHOR]

Published
2022
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37. NFDI4Immuno - Letter of Intent

Author

Busse, Christian E., Babel, Nina, Chang, Hyun-Dong, Dorhoi, Anca, Eugster, Anne, Hummel, Michael, Kammerer, Robert, Küppers, Ralf, Meyer-Hermann, Michael, Nahnsen, Sven, Schmidt, Alexander, Schwab, Nicholas, Bröker, Barbara, Meissner, Felix, Siewert, Katherina, and Zehn, Dietmar

Subjects
NFDI, AIRR, FOS: Clinical medicine, Immunology
Abstract

Binding Letter of Intent of the NFDI4Immuno consortium initiative for the German National Research Data Infrastructure (NFDI) Program.

Published
2020
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38. γδ T-cell Receptors Derived from Breast Cancer–Infiltrating T Lymphocytes Mediate Antitumor Reactivity

Author

Janssen, Anke, Villacorta Hidalgo, Jose, Beringer, Dennis X, Van Dooremalen, Sanne, Febilla, Fernando, Van Diest, Eline, Terrizzi, Antonela Romina, Bronser, Peter, Kock, Sylvia, Schmitt-Gräff, Annette, Werner, Martin, Fisch, Paul, Heise, Kerstin, Follo, Marie, Straetemans, Trudy, Sebestyen, Zsolt, Chudakov, Dmitry M, Kasatskaya, Sofya A., Kuball, Jurgen, Frenkel, Felix E., Ravens, Sarina, Spierings, Eric, Prinz, Immo, Malkovsky, Miroslav, Küppers, Ralf, Graduate School, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Adult, Cancer Research, CIENCIAS MÉDICAS Y DE LA SALUD, T cell, medicine.medical_treatment, Immunology, Medizin, Inmunología, chemical and pharmacologic phenomena, Triple Negative Breast Neoplasms, Biology, Immunotherapy, Adoptive, GAMMA DELTA LYMPHOCYTES, 03 medical and health sciences, 0302 clinical medicine, Immune system, Lymphocytes, Tumor-Infiltrating, Antigen, T-Lymphocyte Subsets, BREAST CANCER, Cell Line, Tumor, medicine, Humans, Receptor, Aged, Aged, 80 and over, Innate immune system, T-cell receptor, High-Throughput Nucleotide Sequencing, hemic and immune systems, Receptors, Antigen, T-Cell, gamma-delta, Immunotherapy, Middle Aged, Coculture Techniques, Healthy Volunteers, Medicina Básica, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Case-Control Studies, Cancer cell, Cancer research, Leukocytes, Mononuclear, Female
Abstract

γδ T cells in human solid tumors remain poorly defined. Here, we describe molecular and functional analyses of T-cell receptors (TCRs) from tumor-infiltrating γδ T lymphocytes (γδ TILs) that were in direct contact with tumor cells in breast cancer lesions from archival material. We observed that the majority of γδ TILs harbored a proinflammatory phenotype and only a minority associated with the expression of IL17. We characterized TCRγ or TCRδ chains of γδ TILs and observed a higher proportion of Vδ2+ T cells compared to other tumor types. By reconstructing matched Vδ2- TCRγ and TCRδ pairs derived from single-cell sequencing, our data suggest that γδ TILs could be active against breast cancer and other tumor types. The reactivity pattern against tumor cells depended on both the TCRγ and TCRδ chains and was independent of additional co-stimulation through other innate immune receptors. We conclude that γδ TILs can mediate tumor reactivity through their individual γδ TCR pairs and that engineered T cells expressing TCRγ and δ chains derived from γδ TILs display potent antitumor reactivity against different cancer cell types and, thus, may be a valuable tool for engineering immune cells for adoptive cell therapies. Fil: Janssen, Anke. University of Utrecht; Países Bajos Fil: Villacorta Hidalgo, Jose. Albert Ludwigs University of Freiburg; Alemania Fil: Beringer, Dennis X. University of Utrecht; Países Bajos Fil: Van Dooremalen, Sanne. University of Utrecht; Países Bajos Fil: Febilla, Fernando. Utrecht University, Netherlands; Argentina Fil: Van Diest, Eline. Utrecht University, Netherlands; Argentina Fil: Terrizzi, Antonela Romina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Fisiología; Argentina Fil: Bronser, Peter. Albert Ludwigs University of Freiburg; Alemania Fil: Kock, Sylvia. Albert Ludwigs University of Freiburg; Alemania Fil: Schmitt-Gräff, Annette. Albert Ludwigs University of Freiburg; Alemania Fil: Werner, Martin. Albert Ludwigs University of Freiburg; Alemania Fil: Fisch, Paul. Albert Ludwigs University of Freiburg; Alemania Fil: Heise, Kerstin. University of Duisburg-Essen; Alemania Fil: Follo, Marie. Albert Ludwigs University of Freiburg; Alemania Fil: Straetemans, Trudy. University of Utrecht; Países Bajos Fil: Sebestyen, Zsolt. University of Utrecht; Países Bajos Fil: Chudakov, Dmitry M. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry; Rusia Fil: Kasatskaya, Sofya A.. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry; Rusia Fil: Kuball, Jurgen. University of Utrecht; Países Bajos Fil: Frenkel, Felix E.. No especifíca; Fil: Ravens, Sarina. Hannover Medical School; Alemania Fil: Spierings, Eric. University of Utrecht; Países Bajos Fil: Prinz, Immo. Hannover Medical School; Alemania Fil: Malkovsky, Miroslav. UW School of Medicine and Public Health; Estados Unidos Fil: Fisch, Paul. Albert Ludwigs University of Freiburg; Alemania Fil: Küppers, Ralf. University of Duisburg-Essen; Alemania

Published
2020

39. The landscape of genomic alterations across childhood cancers

Author

Gröbner, Susanne N., Worst, Barbara C., Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa A., Johann, Pascal D., Balasubramanian, Gnana Prakash, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hübschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jürgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas E., Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Günther H., Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan J., Vassal, Gilles, Witt, Hendrik, Lichter, Peter, Weber, Ursula, Eils, Roland, Korshunov, Andrey, Witt, Olaf, Pfister, Stefan, Reifenberger, Guido, Felsberg, Jörg, von Kalle, Christof, Schmidt, Manfred, Bartholomä, Cynthia, Taylor, Michael, Jones, David, Jäger, Natalie, Korbel, Jan, Stütz, Adrian, Rausch, Tobias, Radlwimmer, Bernhard, Yaspo, Marie-Laure, Lehrach, Hans, Warnatz, Hans-Jörg, Landgraf, Pablo, Brors, Benedikt, Zapatka, Marc, Wagner, Susanne, Haake, Andrea, Richter, Julia, Richter, Gesine, Lawerenz, Chris, Kerssemakers, Jules, Jaeger-Schmidt, Christina, Scholz, Ingrid, Bergmann, Anke K., Borst, Christoph, Burkhardt, Birgit, Claviez, Alexander, Dreyling, Martin, Eberth, Sonja, Einsele, Hermann, Frickhofen, Norbert, Haas, Siegfried, Hansmann, Martin-Leo, Karsch, Dennis, Kneba, Michael, Lisfeld, Jasmin, Mantovani-Löffler, Luisa, Rohde, Marius, Ott, German, Stadler, Christina, Staib, Peter, Stilgenbauer, Stephan, Trümper, Lorenz, Zenz, Thorsten, Kube, Dieter, Küppers, Ralf, Weniger, Marc, Hummel, Michael, Klapper, Wolfram, Kostezka, Ulrike, Lenze, Dido, Möller, Peter, Rosenwald, Andreas, Szczepanowski, Monika, Ammerpohl, Ole, Aukema, Sietse M., Binder, Vera, Hoell, Jessica I., Leich, Ellen, López, Cristina, Nagel, Inga, Pischimariov, Jordan, Rosenstiel, Philip, Schilhabel, Markus, Schreiber, Stefan, Vater, Inga, Wagener, Rabea, Bernhart, Stephan H., Binder, Hans, Doose, Gero, Hoffmann, Steve, Hopp, Lydia, Kretzmer, Helene, Kreuz, Markus, Langenberger, David, Loeffler, Markus, Rosolowski, Maciej, Schlesner, Matthias, Stadler, Peter F., Sungalee, Stephanie, Kratz, Christian P., van Tilburg, Cornelis M., Kramm, Christof M., Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frühwald, Michael, von Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Koster, Jan, Resnick, Adam C., Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela J., Zwijnenburg, Danny A., Raman, Pichai, Weber, Ursula D., Northcott, Paul A., Pajtler, Kristian W., Kool, Marcel, Piro, Rosario M., Korbel, Jan O., Jones, David T. W., Chavez, Lukas, Pfister, Stefan M., Other departments, CCA - Cancer biology and immunology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Oncogenomics

Subjects
0301 basic medicine, Adult, Mutation rate, Mutation/genetics, Adolescent, DNA Copy Number Variations, Medizin, Biology, DNA Copy Number Variations/genetics, Germ-Line Mutation/genetics, Germline, Cohort Studies, 03 medical and health sciences, Young Adult, Germline mutation, Neoplasms/classification, Mutation Rate, Neoplasms, medicine, Humans, Genetic Predisposition to Disease, Molecular Targeted Therapy, ddc:610, Mutation frequency, Child, Germ-Line Mutation, Genetics, Chromothripsis, Multidisciplinary, Genome, Human, Genetic Predisposition to Disease/genetics, Cancer, Genomics, medicine.disease, Diploidy, Human genetics, 3. Good health, ddc, 030104 developmental biology, Mutation (genetic algorithm), Mutation, Genome, Human/genetics, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53
Abstract

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.

Published
2020

40. Identifying genetic lesions in ocular adnexal extranodal marginal zone lymphomas of the malt subtype by whole genome, whole exome and targeted sequencing

Author

Johansson, Patricia, Klein-Hitpaß, Ludger, Budeus, Bettina, Kuhn, Matthias, Lauber, Chris, Seifert, Michael, Roeder, Ingo, Pförtner, Roman, Stuschke, Martin, Dührsen, Ulrich, Eckstein, Anja, Dürig, Jan, and Küppers, Ralf

Subjects
pathogenesis, Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Augenheilkunde, Medizin, Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Hämatologie und Stammzelltransplantation, Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Strahlentherapie, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, JAK/STAT, Article, Medizinische Fakultät » Universitätsklinikum Essen » Institut für Zellbiologie (Tumorforschung), NOTCH, ocular adnexal lymphoma, somatic mutation, ddc:610
Abstract

The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is not fully understood. We performed whole genome sequencing (WGS) and/or whole exome sequencing (WES) for 13 cases of OAML and sequenced 38 genes selected from this analysis in a large cohort of 82 OAML. Besides confirmation of frequent mutations in the genes transducin beta like 1 X-linked receptor 1 (TBL1XR1) and cAMP response element binding protein (CREBBP), we newly identifed JAK3 as a frequently mutated gene in OAML (11% of cases). In our retrospective cohort, JAK3 mutant cases had a shorter progression-free survival compared with unmutated cases. Other newly identified genes recurrently mutated in 5&ndash, 10% of cases included members of the collagen family (collagen type XII alpha 1/2 (COL12A1, COL1A2)) and DOCK8. Evaluation of the WGS data of six OAML did not reveal translocations or a current infection of the lymphoma cells by viruses. Evaluation of the WGS data for copy number aberrations confirmed frequent loss of TNFAIP3, and revealed recurrent gains of the NOTCH target HES4, and of members of the CEBP transcription factor family. Overall, we identified several novel genes recurrently affected by point mutations or copy number alterations, but our study also indicated that the landscape of frequently (&gt, 10% of cases) mutated protein-coding genes in OAML is now largely known.

Published
2020

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