In-depth cell-free DNA sequencing reveals genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive residual disease detection

Sophia Sobesky; Laman Mammadova; Melita Cirillo; Esther E E Drees; Julia Mattlener; Helge Dörr; Janine Altmüller; Zhiyuan Shi; Paul J Bröckelmann; Jonathan Weiss; Stefanie Kreissl; Stephanie Sasse; Roland T Ullrich; Sarah Reinke; Wolfram Klapper; Elena Gerhard-Hartmann; Andreas Rosenwald; Margaretha G M Roemer; Peter Nürnberg; Anton Hagenbeek; Josée M Zijlstra; Dirk Michiel Pegtel; Andreas Engert; Peter Borchmann; Bastian von Tresckow; Sven Borchmann

doi:10.1016/j.medj.2021.09.002

In-depth cell-free DNA sequencing reveals genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive residual disease detection

Med. 2021 Oct 8;2(10):1171-1193.e11. doi: 10.1016/j.medj.2021.09.002.

Authors

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

Affiliations

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.

PMID: 35590205
DOI: 10.1016/j.medj.2021.09.002

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.

Keywords: CAT scale: Translation to patients; Hodgkin lymphoma; cancer; cell-free DNA; circulating DNA; genomics; liquid biopsy; lymphoma; minimal residual disease; response assessment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell-Free Nucleic Acids* / genetics
DNA Copy Number Variations / genetics
Genomics
Hodgkin Disease* / diagnosis
Humans
Neoplasm Recurrence, Local
Neoplasm, Residual / diagnosis
Sequence Analysis, DNA

Substances

Cell-Free Nucleic Acids