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Stecher, Melanie ; Schommers, Philipp Frederik ; Kollan, Christian ; Stoll, Matthias ; Kuhlendahl, Frieder ; Stellbrink, Hans‑Jürgen ; Wasmuth, Jan‑Christian ; Stephan, Christoph ; Hamacher, Laura ; Lehmann, Clara ; Boesecke, Christoph ; Bogner, Johannes ; Esser, Stefan ; Fritzsche, Carlos ; Haberl, Annette ; Hofmann, Christian ; Jensen, Björn ; Schwarze‑Zander, Carolynne ; Platten, Martin ; Fätkenheuer, Gerd ; Schmidt, Daniel ; Gunsenheimer-Bartmeyer, Barbara ; Vehreschild, Jörg Janne
Objective: Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving.
Methods: We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data.
Results: We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR).
Conclusions: Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.
Stecher, Melanie ; Schommers, Philipp Frederik ; Kollan, Christian ; Stoll, Matthias ; Kuhlendahl, Frieder-Johan ; Stellbrink, Hans‑Jürgen ; Wasmuth, Jan‑Christian ; Stephan, Christoph ; Hamacher, Laura ; Lehmann, Clara ; Boesecke, Christoph ; Bogner, Johannes ; Esser, Stefan ; Fritzsche, Carlos ; Haberl, Annette ; Schürmann, Dirk ; Degen, Olaf ; Horst, Heinz August ; Hoffmann, Christian ; Jensen, Björn-Erik Ole ; Schwarze-Zander, Carolynne ; Platten, Martin ; Fätkenheuer, Gerd ; Schmidt, Daniel ; Gunsenheimer-Bartmeyer, Barbara ; Vehreschild, Jörg Janne
Correction to: Infection (2020) 48:723–733 https://doi.org/10.1007/s15010-020-01469-6. The original version of this article unfortunately contained a mistake. In this article the authors Dirk Schürmann at affiliation Charité, University Medicine, Berlin, Olaf Degen at affiliation University Clinic Hamburg Eppendorf, Hamburg and Heinz-August Horst at affiliation University Hospital Schleswig–Holstein, Kiel, Germany were missing from the author list. The original article has been corrected.
Antičić, Tome ; Baatar, B. ; Barna, Daniel ; Bartke, Jerzy ; Behler, Matthias ; Betev, Latchezar ; Białkowska, Helena ; Billmeier, Anja ; Blume, Christoph ; Boimska, Bożena ; Botje, Michiel ; Bracinik, Juraj ; Bramm, Roland ; Brun, René ; Bunčić, Predrag ; Cerny, Vladimír ; Christakoglou, Panagiotis ; Chvala, Ondrej ; Cramer, John G. ; Csató, Péter ; Darmenov, Nikolay ; Dimitrov, Anton ; Dinkelaker, Peter ; Eckardt, Volker ; Filip, Peter ; Flierl, Dominik Bernhard ; Fodor, Zoltán ; Foka, Panagiota ; Freund, Peter ; Friese, Volker ; Gál, József ; Gaździcki, Marek ; Georgopoulos, George ; Gładysz-Dziaduś, Ewa ; Grebieszkow, Katarzyna ; Hegyi, Sándor ; Höhne, Claudia ; Kadija, Krešo ; Karev, Alexandre ; Kolesnikov, Vadim I. ; Kollegger, Thorsten ; Korus, Robert ; Kowalski, Marek ; Kraus, Ingrid ; Kreps, Michal ; Leeuwen, Marco van ; Lévai, Péter ; Litov, Leandr ; Makariev, Martin Vasilev ; Malakhov, Aleksandr I. ; Markert, Christina ; Mateev, Matej D. ; Mayes, Bill W. ; Melkumov, Georgy L. ; Meurer, Christine ; Mischke, André ; Mitrovski, Michael Kosta ; Molnár, József ; Mrówczyński, Stanislaw ; Pálla, Gabriella ; Panagiotou, Apostolos D. ; Panayotov, Dobromir ; Petridis, Athanasios ; Pikna, Miroslav ; Pinsky, Lawrence ; Pühlhofer, Falk ; Reid, Jeffrey G. ; Renfordt, Rainer Arno Ernst ; Retyk, Waldemar ; Roland, Christof ; Roland, Gunther ; Rybczyński, Maciej ; Rybicki, Andrzej ; Sandoval, Andres ; Sann, Hans ; Schmitz, Norbert ; Seyboth, Peter ; Siklér, Ferenc ; Sitar, Branislav ; Skrzypczak, Ewa ; Stefanek, Grzegorz ; Stock, Reinhard ; Ströbele, Herbert ; Šuša, Tatjana ; Szentpétery, Imre ; Sziklai, János ; Trainor, Thomas A. ; Varga, Dezsö ; Vassiliou, Maria ; Veres, Gábor I. ; Vesztergombi, György ; Vranić, Danilo ; Wetzler, Alexander Albert ; Włodarczyk, Zbigniew ; Yoo, In-Kwon ; Zaranek, Jacek ; Zimányi, József
Results are presented on event-by-event fluctuations in transverse momentum of charged particles, produced at forward rapidities in p+p, C+C, Si+Si and Pb+Pb collisions at 158 AGeV. Three different characteristics are discussed: the average transverse momentum of the event, the Phi_pT fluctuation measure and two-particle transverse momentum correlations. In the kinematic region explored, the dynamical fluctuations are found to be small. However, a significant system size dependence of Phi_pT is observed, with the largest value measured in peripheral Pb+Pb interactions. The data are compared with predictions of several models. PACS numbers: 14.20.Jn, 13.75.Cs, 12.39.-x
Mitrovski, Michael K. ; Alt, Christopher ; Antičić, Tome ; Baatar, B. ; Barna, Daniel ; Bartke, Jerzy ; Behler, Matthias ; Betev, Latchezar ; Białkowska, Helena ; Billmeier, Anja ; Blume, Christoph ; Boimska, Bożena ; Botje, Michiel ; Bracinik, Juraj ; Bramm, Roland ; Brun, René ; Bunčić, Predrag ; Cerny, Vladimír ; Christakoglou, Panagiotis ; Chvala, Ondrej ; Cramer, John G. ; Csató, Péter ; Darmenov, Nikolay ; Dimitrov, Anton ; Dinkelaker, Peter ; Eckardt, Volker ; Filip, Peter ; Fischer, Hans Gerhard ; Flierl, Dominik Bernhard ; Fodor, Zoltán ; Foka, Panagiota ; Freund, Peter ; Friese, Volker ; Gál, József ; Gaździcki, Marek ; Georgopoulos, George ; Gładysz-Dziaduś, Ewa ; Hegyi, Sándor ; Höhne, Claudia ; Kadija, Krešo ; Karev, Alexandre ; Kliemant, Michael ; Kniege, Stefan ; Kolesnikov, Vadim I. ; Kollegger, Thorsten ; Kornaś, Ewelina ; Korus, Robert ; Kowalski, Marek ; Kraus, Ingrid ; Kreps, Michal ; Leeuwen, Marco van ; Lévai, Péter ; Litov, Leandr ; Lungwitz, Benjamin ; Makariev, Martin Vasilev ; Malakhov, Aleksandr I. ; Markert, Christina ; Mateev, Matej D. ; Mayes, Bill W. ; Melkumov, Georgy L. ; Meurer, Christine ; Mischke, André ; Mitrovski, Michael Kosta ; Molnár, József ; Mrówczyński, Stanislaw ; Pálla, Gabriella ; Panagiotou, Apostolos D. ; Panayotov, Dobromir ; Perl, Katarzyna ; Petridis, Athanasios ; Pikna, Miroslav ; Pinsky, Lawrence ; Pühlhofer, Falk ; Reid, Jeffrey G. ; Renfordt, Rainer Arno Ernst ; Retyk, Waldemar ; Richard, Agnes Carol Joanna ; Roland, Christof ; Roland, Gunther ; Rybczyński, Maciej ; Rybicki, Andrzej ; Sandoval, Andres ; Sann, Hans ; Schmitz, Norbert ; Seyboth, Peter ; Siklér, Ferenc ; Sitar, Branislav ; Skrzypczak, Ewa ; Stefanek, Grzegorz ; Stock, Reinhard ; Ströbele, Herbert ; Šuša, Tatjana ; Szentpétery, Imre ; Sziklai, János ; Trainor, Thomas A. ; Varga, Dezsö ; Vassiliou, Maria ; Veres, Gábor I. ; Vesztergombi, György ; Vranić, Danilo ; Wenig, Siegfried ; Wetzler, Alexander Albert ; Włodarczyk, Zbigniew ; Yoo, In-Kwon ; Zaranek, Jacek ; Zimányi, József
A non-monotonic energy dependence of the K + / pi + ratio with a sharp maximum close to 30 A GeV is observed in central Pb+Pb collisions. Within a statistical model of the early stage, this is interpreted as a sign of the phase transition to a QGP, which causes a sharp change in the energy dependence of the strangeness to entropy ratio. This observation naturally motivates us to study the production of multistrange hyperons (Xi, Omega) as a function of the beam energy. Furthermore it was suggested that the kinematic freeze-out of Omega takes place directly at QGP hadronization. If this is indeed the case, the transverse momentum spectra of the Omega directly reflect the transverse expansion velocity of a hadronizing QGP. In this report we show preliminary NA49 results on Omega - and Omega + production in central Pb+Pb collisions at 40 and 158 A GeV and compare them to measurements of Xi - and Xi + production in central Pb+Pb collisions at 30, 40, 80 and 158 A GeV.
Gabler, Matthias ; Kramer, Jan ; Schmidt, Jurema ; Pollinger, Julius Carl ; Weber, Julia ; Kaiser, Astrid ; Löhr, Frank ; Proschak, Ewgenij ; Schubert-Zsilavecz, Manfred ; Merk, Daniel
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
Alt, Christopher ; Antičić, Tome ; Baatar, B. ; Barna, Daniel ; Bartke, Jerzy ; Behler, Matthias ; Betev, Latchezar ; Białkowska, Helena ; Billmeier, Anja ; Blume, Christoph ; Boimska, Bożena ; Botje, Michiel ; Bracinik, Juraj ; Bramm, Roland ; Brun, René ; Bunčić, Predrag ; Cerny, Vladimír ; Christakoglou, Panagiotis ; Chvala, Ondrej ; Cramer, John G. ; Csató, Péter ; Darmenov, Nikolay ; Dimitrov, Anton ; Dinkelaker, Peter ; Eckardt, Volker ; Filip, Peter ; Flierl, Dominik Bernhard ; Fodor, Zoltán ; Foka, Panagiota ; Freund, Peter ; Friese, Volker ; Gál, József ; Gaździcki, Marek ; Georgopoulos, George ; Gładysz-Dziaduś, Ewa ; Grebieszkow, Katarzyna ; Hegyi, Sándor ; Höhne, Claudia ; Kadija, Krešo ; Karev, Alexandre ; Kliemant, Michael ; Kniege, Stefan ; Kolesnikov, Vadim I. ; Kollegger, Thorsten ; Kornas, Ewelina ; Korus, Robert ; Kowalski, Marek ; Kraus, Ingrid ; Kreps, Michal ; Leeuwen, Marco van ; Lévai, Péter ; Litov, Leandr ; Lungwitz, Benjamin ; Makariev, Martin Vasilev ; Malakhov, Aleksandr I. ; Markert, Christina ; Mateev, Matej D. ; Mayes, Bill W. ; Melkumov, Georgy L. ; Meurer, Christine ; Mischke, André ; Mitrovski, Michael Kosta ; Molnár, József ; Mrówczyński, Stanislaw ; Pálla, Gabriella ; Panagiotou, Apostolos D. ; Panayotov, Dobromir ; Petridis, Athanasios ; Pikna, Miroslav ; Pinsky, Lawrence ; Pühlhofer, Falk ; Reid, Jeffrey G. ; Renfordt, Rainer Arno Ernst ; Richard, Agnes Carol Joanna ; Roland, Christof ; Roland, Gunther ; Rybczyński, Maciej ; Rybicki, Andrzej ; Sandoval, Andres ; Sann, Hans ; Schmitz, Norbert ; Seyboth, Peter ; Siklér, Ferenc ; Sitar, Branislav ; Skrzypczak, Ewa ; Stefanek, Grzegorz ; Stock, Reinhard ; Ströbele, Herbert ; Šuša, Tatjana ; Szentpétery, Imre ; Sziklai, János ; Trainor, Thomas A. ; Varga, Dezsö ; Vassiliou, Maria ; Veres, Gábor I. ; Vesztergombi, György ; Vranić, Danilo ; Wetzler, Alexander Albert ; Włodarczyk, Zbigniew ; Yoo, In-Kwon ; Zaranek, Jacek ; Zimányi, József
Results are presented on event-by-event electric charge fluctuations in central Pb+Pb collisions at 20, 30, 40, 80 and 158 AGeV. The observed fluctuations are close to those expected for a gas of pions correlated by global charge conservation only. These fluctuations are considerably larger than those calculated for an ideal gas of deconfined quarks and gluons. The present measurements do not necessarily exclude reduced fluctuations from a quark-gluon plasma because these might be masked by contributions from resonance decays.
Antičić, Tome ; Baatar, B. ; Barna, Daniel ; Bartke, Jerzy ; Behler, Matthias ; Betev, Latchezar ; Białkowska, Helena ; Billmeier, Anja ; Blume, Christoph ; Boimska, Bożena ; Botje, Michiel ; Bracinik, Juraj ; Bramm, Roland ; Brun, René ; Bunčić, Predrag ; Cerny, Vladimír ; Christakoglou, Panagiotis ; Chvala, Ondrej ; Cramer, John G. ; Csató, Péter ; Darmenov, Nikolay ; Dimitrov, Anton ; Dinkelaker, Peter ; Eckardt, Volker ; Filip, Peter ; Flierl, Dominik Bernhard ; Fodor, Zoltán ; Foka, Panagiota ; Freund, Peter ; Friese, Volker ; Gál, József ; Gaździcki, Marek ; Georgopoulos, George ; Gładysz-Dziaduś, Ewa ; Hegyi, Sándor ; Höhne, Claudia ; Kadija, Krešo ; Karev, Alexandre ; Kolesnikov, Vadim I. ; Kollegger, Thorsten ; Kornas, Ewelina ; Korus, Robert ; Kowalski, Marek ; Kraus, Ingrid ; Kreps, Michal ; Leeuwen, Marco van ; Lévai, Péter ; Litov, Leandr ; Makariev, Martin Vasilev ; Malakhov, Aleksandr I. ; Markert, Christina ; Mateev, Matej D. ; Mayes, Bill W. ; Melkumov, Georgy L. ; Meurer, Christine ; Mischke, André ; Mitrovski, Michael Kosta ; Molnár, József ; Mrówczyński, Stanislaw ; Pálla, Gabriella ; Panagiotou, Apostolos D. ; Panayotov, Dobromir ; Perl, Katarzyna ; Petridis, Athanasios ; Pikna, Miroslav ; Pinsky, Lawrence ; Pühlhofer, Falk ; Reid, Jeffrey G. ; Renfordt, Rainer Arno Ernst ; Retyk, Waldemar ; Roland, Christof ; Roland, Gunther ; Rybczyński, Maciej ; Rybicki, Andrzej ; Sandoval, Andres ; Sann, Hans ; Schmitz, Norbert ; Seyboth, Peter ; Siklér, Ferenc ; Sitar, Branislav ; Skrzypczak, Ewa ; Stefanek, Grzegorz ; Stock, Reinhard ; Ströbele, Herbert ; Šuša, Tatjana ; Szentpétery, Imre ; Sziklai, János ; Trainor, Thomas A. ; Varga, Dezsö ; Vassiliou, Maria ; Veres, Gábor I. ; Vesztergombi, György ; Vranić, Danilo ; Wetzler, Alexander Albert ; Włodarczyk, Zbigniew ; Yoo, In-Kwon ; Zaranek, Jacek ; Zimányi, József
Production of Lambda and Antilambda hyperons was measured in central Pb-Pb collisions at 40, 80, and 158 A GeV beam energy on a fixed target. Transverse mass spectra and rapidity distributions are given for all three energies. The Lambda/pi ratio at mid-rapidity and in full phase space shows a pronounced maximum between the highest AGS and 40 A GeV SPS energies, whereas the anti-Lambda}/pi ratio exhibits a monotonic increase. PACS numbers: 25.75.-q
Willems, Laurent Maximilian ; Rosenow, Felix ; Schubert-Bast, Susanne ; Kurlemann, Gerhard ; Zöllner, Johann Philipp ; Bast, Thomas ; Bertsche, Astrid ; Bettendorf, Ulrich ; Ebrahimi-Fakhari, Daniel ; Grau, Janina ; Hahn, Andreas ; Hartmann, Hans ; Hertzberg, Christoph ; Hornemann, Frauke ; Immisch, Ilka ; Jacobs-LeVan, Julia ; Klein, Karl Martin ; Klotz, Kerstin Alexandra ; Kluger, Gerhard ; Knake, Susanne ; Knuf, Markus ; Marquard, Klaus ; Mayer, Thomas ; Meyer, Sascha ; Muhle, Hiltrud ; Müller-Schlüter, Karen ; Podewils, Felix von ; Ruf, Susanne ; Sauter, Matthias ; Schäfer, Hannah ; Schlump, Jan-Ulrich ; Syrbe, Steffen ; Thiels, Charlotte ; Trollmann, Regina ; Wiemer-Kruel, Adelheid ; Wilken, Bernd ; Zukunft, Bianca ; Strzelczyk, Adam
Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions: From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
Gröschel, Stefan ; Hübschmann, Daniel ; Raimondi, Francesco ; Horak, Peter ; Warsow, Gregor ; Fröhlich, Martina ; Klink, Barbara ; Gieldon, Laura ; Hutter, Barbara ; Kleinheinz, Kortine ; Bonekamp, David ; Marschal, Oliver ; Chudasama, Priya ; Mika, Jagoda ; Groth, Marie ; Uhrig, Sebastian ; Krämer, Stephen ; Heining, Christoph ; Heilig, Christoph E. ; Richter, Daniela ; Reisinger, Eva ; Pfütze, Katrin ; Eils, Roland ; Wolf, Stephan ; Kalle, Christof von ; Brandts, Christian Hubertus ; Scholl, Claudia ; Weichert, Wilko ; Richter, Stephan ; Bauer, Sebastian ; Penzel, Roland ; Schröck, Evelin ; Stenzinger, Albrecht ; Schlenk, Richard Friedrich ; Brors, Benedikt ; Russell, Robert B. ; Glimm, Hanno ; Schlesner, Matthias ; Fröhling, Stefan
Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
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 Martin ; 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 ; Höll, Jessica ; Hummel, Michael ; Korbel, Jan Oliver ; 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 Andrèe ; Zapatka, Marc ; Eils, Roland ; Lichter, Peter ; Löffler, Markus ; Möller, Peter ; Trümper, Lorenz ; Klapper, Wolfram ; Hoffmann, Steve ; Küppers, Ralf ; Burkhardt, Birgit ; Schlesner, Matthias ; Siebert, Reiner
Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.