Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling

Stefan K. Alig, Mohammad Shahrokh Esfahani, Andrea Garofalo, Michael Yu Li, Cédric Rossi, Tim Flerlage, Jamie E. Flerlage, Ragini Adams, Michael S. Binkley, Navika Shukla, Michael C. Jin, Mari Olsen, Adèle Telenius, Jurik A. Mutter, Joseph G. Schroers-Martin, Brian J. Sworder, Shinya Rai, Daniel A. King, Andre Schultz, Jan Bögeholz, Shengqin Su, Karan R. Kathuria, Chih Long Liu, Xiaoman Kang, Maya J. Strohband, Deanna Langfitt, Kristine Faye Pobre-Piza, Sherri Surman, Feng Tian, Valeria Spina, Thomas Tousseyn, Lieselot Buedts, Richard Hoppe, Yasodha Natkunam, Luc-Matthieu Fornecker, Sharon M. Castellino, Ranjana Advani, Davide Rossi, Ryan Lynch, Hervé Ghesquières, Olivier Casasnovas, David M. Kurtz, Lianna J. Marks, Michael P. Link, Marc André, Peter Vandenberghe, Christian Steidl, Maximilian Diehn () and Ash A. Alizadeh ()
Additional contact information
Stefan K. Alig: Stanford University
Mohammad Shahrokh Esfahani: Stanford University
Andrea Garofalo: Stanford University
Michael Yu Li: British Columbia Cancer
Cédric Rossi: Stanford University
Tim Flerlage: St Jude Children’s Research Hospital
Jamie E. Flerlage: St Jude Children’s Research Hospital
Ragini Adams: Stanford University
Michael S. Binkley: Stanford University Medical Center
Navika Shukla: Stanford University
Michael C. Jin: Stanford University
Mari Olsen: Stanford University
Adèle Telenius: British Columbia Cancer
Jurik A. Mutter: Stanford University
Joseph G. Schroers-Martin: Stanford University
Brian J. Sworder: Stanford University
Shinya Rai: British Columbia Cancer
Daniel A. King: Stanford University
Andre Schultz: Stanford University
Jan Bögeholz: Stanford University
Shengqin Su: Stanford University Medical Center
Karan R. Kathuria: Stanford University
Chih Long Liu: Stanford University
Xiaoman Kang: Stanford University
Maya J. Strohband: Stanford University
Deanna Langfitt: St Jude Children’s Research Hospital
Kristine Faye Pobre-Piza: St Jude Children’s Research Hospital
Sherri Surman: St Jude Children’s Research Hospital
Feng Tian: Stanford University
Valeria Spina: Laboratory of Molecular Diagnostics, Department of Medical Genetics EOLAB
Thomas Tousseyn: KU Leuven
Lieselot Buedts: KU Leuven
Richard Hoppe: Stanford University Medical Center
Yasodha Natkunam: Stanford University
Luc-Matthieu Fornecker: Institut de Cancérologie Strasbourg Europe (ICANS) and University of Strasbourg
Sharon M. Castellino: Emory University, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta
Ranjana Advani: Stanford University
Davide Rossi: Ente Ospedaliero Cantonale
Ryan Lynch: Fred Hutchinson Cancer Research Center
Hervé Ghesquières: Hospices Civils de Lyon
Olivier Casasnovas: University Hospital F. Mitterrand and Inserm UMR 1231
David M. Kurtz: Stanford University
Lianna J. Marks: Stanford University
Michael P. Link: Stanford University
Marc André: CHU UCL Namur
Peter Vandenberghe: KU Leuven
Christian Steidl: British Columbia Cancer
Maximilian Diehn: Stanford University Medical Center
Ash A. Alizadeh: Stanford University

Nature, 2024, vol. 625, issue 7996, 778-787

Abstract: Abstract The scarcity of malignant Hodgkin and Reed–Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1–4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed–Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Date: 2024
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DOI: 10.1038/s41586-023-06903-x

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