Sophia Sobesky1, Laman Mammadova1, Melita Cirillo2, Esther E E Drees3, Julia Mattlener1, Helge Dörr1, Janine Altmüller4, Zhiyuan Shi5, Paul J Bröckelmann1, Jonathan Weiss5, Stefanie Kreissl1, Stephanie Sasse6, Roland T Ullrich5, Sarah Reinke7, Wolfram Klapper7, Elena Gerhard-Hartmann8, Andreas Rosenwald8, Margaretha G M Roemer9, Peter Nürnberg4, Anton Hagenbeek9, Josée M Zijlstra9, Dirk Michiel Pegtel10, Andreas Engert1, Peter Borchmann1, Bastian von Tresckow11, Sven Borchmann12. 1. Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Köln, Germany; Cancer Center Cologne Essen - Partner Site Cologne, CIO Cologne, University of Cologne, Köln, Germany; German Hodgkin Study Group, Cologne, Germany. 2. University of Western Australia and Royal Perth Hospital, Perth, Australia. 3. Amsterdam UMC, Vrije Universiteit Amsterdam, Exosomes Research Group, Department of Pathology, Cancer Center Amsterdam, Amsterdam, the Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, Amsterdam, the Netherlands. 4. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany. 5. Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Köln, Germany; Cancer Center Cologne Essen - Partner Site Cologne, CIO Cologne, University of Cologne, Köln, Germany. 6. Department IV of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, RWTH Aachen University, Aachen, Germany. 7. University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. 8. Department of Pathology, University of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken, Würzburg, Germany. 9. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, Amsterdam, the Netherlands. 10. Amsterdam UMC, Vrije Universiteit Amsterdam, Exosomes Research Group, Department of Pathology, Cancer Center Amsterdam, Amsterdam, the Netherlands. 11. German Hodgkin Study Group, Cologne, Germany; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK partner site Essen), Essen, Germany; Cancer Center Cologne Essen - Partner Site Essen, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany. 12. Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Köln, Germany; Cancer Center Cologne Essen - Partner Site Cologne, CIO Cologne, University of Cologne, Köln, Germany; German Hodgkin Study Group, Cologne, Germany. Electronic address: sven.borchmann@uk-koeln.de.
Abstract
BACKGROUND: Individualization of treatment in Hodgkin's lymphoma is necessary to improve cure rates and reduce treatment side effects. Currently, it is hindered by a lack of genomic characterization and sensitive molecular response assessment. Sequencing of cell-free DNA is a powerful strategy to understand the cancer genome and can be used for extremely sensitive disease monitoring. In Hodgkin's lymphoma, a high proportion of cell-free DNA is tumor-derived, whereas traditional tumor biopsies only contain a little tumor-derived DNA. METHODS: We comprehensively genotype and assess minimal residual disease in 121 patients with baseline plasma as well as 77 follow-up samples from a subset of patients with our targeted cell-free DNA sequencing platform. FINDINGS: We present an integrated landscape of mutations and copy number variations in Hodgkin's lymphoma. In addition, we perform a deep analysis of mutational processes driving Hodgkin's lymphoma, investigate the clonal structure of Hodgkin's lymphoma, and link several genotypes to Hodgkin's lymphoma phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cell-free DNA sequencing, as early as a week after treatment initiation, predicts treatment response and progression-free survival, allowing highly improved treatment guidance and relapse prediction. CONCLUSIONS: Our targeted cell-free DNA sequencing platform reveals the genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive detection of minimal residual disease. FUNDING: Mildred Scheel School of Oncology Aachen-Bonn-Cologne-Düsseldorf MD Research Stipend, Next Generation Sequencing Competence Network grant 423957469, Deutsche Krebshilfe grant 70112502, Deutsche Forschungsgemeinschaft (DFG) grant EN 179/13-1, the HL MRD consortium, and the Frau-Weiskam und Christel Ruranski-Stiftung.
BACKGROUND: Individualization of treatment in Hodgkin's lymphoma is necessary to improve cure rates and reduce treatment side effects. Currently, it is hindered by a lack of genomic characterization and sensitive molecular response assessment. Sequencing of cell-free DNA is a powerful strategy to understand the cancer genome and can be used for extremely sensitive disease monitoring. In Hodgkin's lymphoma, a high proportion of cell-free DNA is tumor-derived, whereas traditional tumor biopsies only contain a little tumor-derived DNA. METHODS: We comprehensively genotype and assess minimal residual disease in 121 patients with baseline plasma as well as 77 follow-up samples from a subset of patients with our targeted cell-free DNA sequencing platform. FINDINGS: We present an integrated landscape of mutations and copy number variations in Hodgkin's lymphoma. In addition, we perform a deep analysis of mutational processes driving Hodgkin's lymphoma, investigate the clonal structure of Hodgkin's lymphoma, and link several genotypes to Hodgkin's lymphoma phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cell-free DNA sequencing, as early as a week after treatment initiation, predicts treatment response and progression-free survival, allowing highly improved treatment guidance and relapse prediction. CONCLUSIONS: Our targeted cell-free DNA sequencing platform reveals the genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive detection of minimal residual disease. FUNDING: Mildred Scheel School of Oncology Aachen-Bonn-Cologne-Düsseldorf MD Research Stipend, Next Generation Sequencing Competence Network grant 423957469, Deutsche Krebshilfe grant 70112502, Deutsche Forschungsgemeinschaft (DFG) grant EN 179/13-1, the HL MRD consortium, and the Frau-Weiskam und Christel Ruranski-Stiftung.
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Authors: Esther E E Drees; Yvonne W S Jauw; Erik van Dijk; Sven Borchmann; Sandra A W M Verkuijlen; Phylicia Stathi; Nils J Groenewegen; Nathalie J Hijmering; Daniella R A I Berry; Eric J Meershoek; Danielle Hoogmoed; Anne Kwakman; Tessa J Molenaar; Dirk M Pegtel; Bauke Ylstra; Daphne de Jong; Josée M Zijlstra; Margaretha G M Roemer Journal: Hemasphere Date: 2022-07-04
Authors: Diede A G van Bladel; Wendy B C Stevens; Michiel van den Brand; Leonie I Kroeze; Patricia J T A Groenen; J Han J M van Krieken; Konnie M Hebeda; Blanca Scheijen Journal: Cancers (Basel) Date: 2022-06-30 Impact factor: 6.575