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Dive into the research topics where Stefan Gröschel is active.

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Featured researches published by Stefan Gröschel.


Journal of Clinical Oncology | 2010

Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.

Sanne Lugthart; Stefan Gröschel; H. Berna Beverloo; Sabine Kayser; Shama van Zelderen-Bhola; Gert J. Ossenkoppele; Edo Vellenga; Eva van den Berg-de Ruiter; Urs Schanz; Gregor Verhoef; Peter Vandenberghe; Augustin Ferrant; Claus-Henning Köhne; Michael Pfreundschuh; Heinz A. Horst; Elisabeth Koller; Marie von Lilienfeld-Toal; Martin Bentz; Arnold Ganser; Brigitte Schlegelberger; Martine Jotterand; Jürgen Krauter; Thomas Pabst; Matthias Theobald; Richard F. Schlenk; Ruud Delwel; Konstanze Döhner; Bob Löwenberg; Hartmut Döhner

PURPOSE Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved. PATIENTS AND METHODS Cytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction. RESULTS 3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3). CONCLUSION Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.


Cancer Cell | 2016

Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes

Pascal Johann; Serap Erkek; Marc Zapatka; Kornelius Kerl; Ivo Buchhalter; Volker Hovestadt; David T. W. Jones; Dominik Sturm; Carl Hermann; Maia Segura Wang; Andrey Korshunov; Marina Rhyzova; Susanne Gröbner; Sebastian Brabetz; Lukas Chavez; Susanne Bens; Stefan Gröschel; Fabian Kratochwil; Andrea Wittmann; Laura Sieber; Christina Geörg; Stefan Wolf; Katja Beck; Florian Oyen; David Capper; Peter van Sluis; Richard Volckmann; Jan Koster; Rogier Versteeg; Andreas von Deimling

Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.


Nature | 2016

Active medulloblastoma enhancers reveal subgroup-specific cellular origins

Charles Y. Lin; Serap Erkek; Yiai Tong; Linlin Yin; Alexander J. Federation; Marc Zapatka; Parthiv Haldipur; Daisuke Kawauchi; Thomas Risch; Hans Jörg Warnatz; Barbara C. Worst; Bensheng Ju; Brent A. Orr; Rhamy Zeid; Donald R. Polaski; Maia Segura-Wang; Sebastian M. Waszak; David T. W. Jones; Marcel Kool; Volker Hovestadt; Ivo Buchhalter; Laura Sieber; Pascal Johann; Lukas Chavez; Stefan Gröschel; Marina Ryzhova; Andrey Korshunov; Wenbiao Chen; Victor V. Chizhikov; Kathleen J. Millen

Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.


Genes, Chromosomes and Cancer | 2016

Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load, and survival.

Jan Budczies; Michael Bockmayr; Carsten Denkert; Frederick Klauschen; Stefan Gröschel; Silvia Darb-Esfahani; Nicole Pfarr; Jonas Leichsenring; Maristela L. Onozato; Jochen K. Lennerz; Manfred Dietel; Stefan Fröhling; Peter Schirmacher; A. John Iafrate; Wilko Weichert; Albrecht Stenzinger

Inhibition of the PD‐L1 (CD274) – PD‐1 axis has emerged as a powerful cancer therapy that prevents evasion of tumor cells from the immune system. While immunohistochemical detection of PD‐L1 was introduced as a predictive biomarker with variable power, much less is known about copy number alterations (CNA) affecting PD‐L1 and their associations with expression levels, mutational load, and survival. To gain insight, we employed The Cancer Genome Atlas (TCGA) datasets to comprehensively analyze 22 major cancer types for PD‐L1 CNAs. We observed a diverse landscape of PD‐L1 CNAs, which affected focal regions, chromosome 9p or the entire chromosome 9. Deletions of PD‐L1 were more frequent than gains (31% vs. 12%) with deletions being most prevalent in melanoma and non‐small cell lung cancer. Copy number gains most frequently occurred in ovarian cancer, head and neck cancer, bladder cancer, cervical and endocervical cancer, sarcomas, and colorectal cancers. Fine‐mapping of the genetic architecture revealed specific recurrently amplified and deleted core regions across cancers with putative biological and clinical consequences. PD‐L1 CNAs correlated significantly with PD‐L1 mRNA expression changes in many cancer types, and tumors with PD‐L1 gains harbored significantly higher mutational load compared to non‐amplified cases (median: 78 non‐synonymous mutations vs. 40, P = 7.1e‐69). Moreover, we observed that, in general, both PD‐L1 amplifications and deletions were associated with dismal prognosis. In conclusion, PD‐L1 CNAs, in particular PD‐L1 copy number gains, represent frequent genetic alterations across many cancers, which influence PD‐L1 expression levels, are associated with higher mutational loads, and may be exploitable as predictive biomarker for immunotherapy regimens.


Blood | 2016

An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation

Roberto Avellino; Marije Havermans; Claudia Erpelinck; Mathijs A. Sanders; Remco M. Hoogenboezem; Harmen J.G. van de Werken; Elwin Rombouts; Kirsten van Lom; Paulette van Strien; Claudia Gebhard; Michael Rehli; John E. Pimanda; Dominik Beck; Stefan J. Erkeland; Thijs Kuiken; Hans de Looper; Stefan Gröschel; Ivo P. Touw; Eric M. J. Bindels; Ruud Delwel

Neutrophilic differentiation is dependent on CCAAT enhancer-binding protein α (C/EBPα), a transcription factor expressed in multiple organs including the bone marrow. Using functional genomic technologies in combination with clustered regularly-interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 genome editing and in vivo mouse modeling, we show that CEBPA is located in a 170-kb topological-associated domain that contains 14 potential enhancers. Of these, 1 enhancer located +42 kb from CEBPA is active and engages with the CEBPA promoter in myeloid cells only. Germ line deletion of the homologous enhancer in mice in vivo reduces Cebpa levels exclusively in hematopoietic stem cells (HSCs) and myeloid-primed progenitor cells leading to severe defects in the granulocytic lineage, without affecting any other Cebpa-expressing organ studied. The enhancer-deleted progenitor cells lose their myeloid transcription program and are blocked in differentiation. Deletion of the enhancer also causes loss of HSC maintenance. We conclude that a single +42-kb enhancer is essential for CEBPA expression in myeloid cells only.


Leukemia | 2016

Cooperation of BRAF F595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling

M Kordes; Michael Röring; Christoph Heining; Sandra Braun; Barbara Hutter; Daniela Richter; Christina Geörg; Claudia Scholl; Stefan Gröschel; W Roth; Andreas Rosenwald; E Geissinger; C. Von Kalle; Dirk Jäger; Benedikt Brors; Wilko Weichert; C. Grüllich; Hanno Glimm; Tilman Brummer; Stefan Fröhling

Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D594F595G596 motif cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAFF595L is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAFF595L, as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors.


Cold Spring Harb Mol Case Stud | 2016

Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification

Stefan Gröschel; Martin Bommer; Barbara Hutter; Jan Budczies; David Bonekamp; Christoph Heining; Peter Horak; Martina Fröhlich; Sebastian Uhrig; Daniel Hübschmann; Christina Geörg; Daniela Richter; Nicole Pfarr; Katrin Pfütze; Stephan Wolf; Peter Schirmacher; Dirk Jäger; Christof von Kalle; Benedikt Brors; Hanno Glimm; Wilko Weichert; Albrecht Stenzinger; Stefan Fröhling

Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal high-level amplification of Chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3). Integrated analysis of molecular data and histopathology provided a rationale for immune checkpoint inhibitor (ICI) therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Histopathological analyses ruled out sarcoma and established the diagnosis of a poorly differentiated adenocarcinoma. Although neither histopathology nor molecular data were able to pinpoint the tissue of origin, our analyses established several differential diagnoses including triple-negative breast cancer (TNBC). We analyzed 157 TNBC samples from The Cancer Genome Atlas, revealing PDL1 copy number gains coinciding with excessive PDL1 mRNA expression in 24% of cases. Collectively, these results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of PDL1 amplification for immune checkpoint inhibitors (ICIs), and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers.


International Journal of Cancer | 2017

Precision Oncology Based on Omics Data: The NCT Heidelberg Experience

Peter Horak; Barbara Klink; Christoph Heining; Stefan Gröschel; Barbara Hutter; Martina Fröhlich; Sebastian Uhrig; Daniel Hübschmann; Matthias Schlesner; Roland Eils; Daniela Richter; Katrin Pfütze; Christina Geörg; Bettina Meißburger; Stephan Wolf; Angela Schulz; Roland Penzel; Esther Herpel; Martina Kirchner; Amelie Lier; Volker Endris; Stephan Singer; Peter Schirmacher; Wilko Weichert; Albrecht Stenzinger; Richard F. Schlenk; Evelin Schröck; Benedikt Brors; Christof von Kalle; Hanno Glimm

Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on increasingly accurate, high‐resolution molecular diagnostics as well as the functional and mechanistic understanding of individual tumors. While molecular stratification of patients can be achieved through different means, a promising approach is next‐generation sequencing of tumor DNA and RNA, which can reveal genomic alterations that have immediate clinical implications. Furthermore, certain genetic alterations are shared across multiple histologic entities, raising the fundamental question of whether tumors should be treated by molecular profile and not tissue of origin. We here describe MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a clinically applicable platform for prospective, biology‐driven stratification of younger adults with advanced‐stage cancer across all histologies and patients with rare tumors. We illustrate how a standardized workflow for selection and consenting of patients, sample processing, whole‐exome/genome and RNA sequencing, bioinformatic analysis, rigorous validation of potentially actionable findings, and data evaluation by a dedicated molecular tumor board enables categorization of patients into different intervention baskets and formulation of evidence‐based recommendations for clinical management. Critical next steps will be to increase the number of patients that can be offered comprehensive molecular analysis through collaborations and partnering, to explore ways in which additional technologies can aid in patient stratification and individualization of treatment, to stimulate clinically guided exploratory research projects, and to gradually move away from assessing the therapeutic activity of targeted interventions on a case‐by‐case basis toward controlled clinical trials of genomics‐guided treatments.


Annals of Oncology | 2016

Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma

Sebastian M. Dieter; Christoph Heining; Abbas Agaimy; Daniel Huebschmann; David Bonekamp; Barbara Hutter; K. R. Ehrenberg; Martina Fröhlich; Matthias Schlesner; Claudia Scholl; H. P. Schlemmer; Stephan Wolf; A. Mavratzas; C. S. Jung; Stefan Gröschel; C. Von Kalle; Roland Eils; Benedikt Brors; Roland Penzel; Mark Kriegsmann; D. E. Reuss; Peter Schirmacher; Albrecht Stenzinger; P. A. Federspil; Wilko Weichert; Hanno Glimm; Stefan Fröhling

Background Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Patients and methods We used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.D579del) as potentially druggable target in this patient and carried out cancer hotspot panel sequencing to detect secondary resistance-conferring mutations in KIT. Furthermore, as a step towards clinical exploitation of the recently described signatures of mutational processes in cancer genomes, we established and applied a novel bioinformatics algorithm that enables supervised analysis of the mutational catalogs of individual tumors. Results Molecularly guided treatment with imatinib in analogy to the management of gastrointestinal stromal tumor (GIST) resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. KIT dependency was further validated by a secondary KIT exon 17 mutation (c.2459_2462delATTCinsG, p.D820_S821delinsG) that was detected upon tumor progression after 10 months of imatinib treatment and provided a rationale for salvage therapy with regorafenib, which has activity against KIT exon 11/17 mutant GIST. Conclusions These observations highlight the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscore that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.BACKGROUND Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. PATIENTS AND METHODS We used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.D579del) as potentially druggable target in this patient and carried out cancer hotspot panel sequencing to detect secondary resistance-conferring mutations in KIT. Furthermore, as a step towards clinical exploitation of the recently described signatures of mutational processes in cancer genomes, we established and applied a novel bioinformatics algorithm that enables supervised analysis of the mutational catalogs of individual tumors. RESULTS Molecularly guided treatment with imatinib in analogy to the management of gastrointestinal stromal tumor (GIST) resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. KIT dependency was further validated by a secondary KIT exon 17 mutation (c.2459_2462delATTCinsG, p.D820_S821delinsG) that was detected upon tumor progression after 10 months of imatinib treatment and provided a rationale for salvage therapy with regorafenib, which has activity against KIT exon 11/17 mutant GIST. CONCLUSIONS These observations highlight the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscore that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.


Clinical Cancer Research | 2017

Targeting fibroblast growth factor receptor 1 for treatment of soft-tissue sarcoma.

Priya Chudasama; Marcus Renner; Melanie Straub; Sadaf S. Mughal; Barbara Hutter; Zeynep Kosaloglu; Ron Schweßinger; Matthias Scheffler; Ingo Alldinger; Simon Schimmack; Thorsten Persigehl; Carsten Kobe; Dirk Jäger; Christof von Kalle; Peter Schirmacher; Marie Beckhaus; Stephan Wolf; Christoph Heining; Stefan Gröschel; Jürgen Wolf; Benedikt Brors; Wilko Weichert; Hanno Glimm; Claudia Scholl; Gunhild Mechtersheimer; Katja Specht; Stefan Fröhling

Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS. Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis. Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK–ERK1/2 axis as critical FGFR1 effector pathway. Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK–ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962–73. ©2016 AACR.

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Stefan Fröhling

German Cancer Research Center

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Hanno Glimm

German Cancer Research Center

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Benedikt Brors

German Cancer Research Center

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Christoph Heining

German Cancer Research Center

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Albrecht Stenzinger

University Hospital Heidelberg

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Barbara Hutter

German Cancer Research Center

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Claudia Scholl

German Cancer Research Center

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Daniela Richter

German Cancer Research Center

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Peter Schirmacher

University Hospital Heidelberg

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Christof von Kalle

German Cancer Research Center

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