Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling

• 成果类型: Article
• 署名作者: Alig, Stefan K.; Shahrokh Esfahani, Mohammad; Garofalo, Andrea; Li, Michael Yu; Rossi, Cedric; Flerlage, Tim; Flerlage, Jamie E.; Adams, Ragini; Binkley, Michael S.; Shukla, Navika; Jin, Michael C.; Olsen, Mari; Telenius, Adele; Mutter, Jurik A.; Schroers-Martin, Joseph G.; Sworder, Brian J.; Rai, Shinya; King, Daniel A.; Schultz, Andre; Bogeholz, Jan; Su, Shengqin; Kathuria, Karan R.; Liu, Chih Long; Kang, Xiaoman; Strohband, Maya J.; Langfitt, Deanna; Pobre-Piza, Kristine Faye; Surman, Sherri; Tian, Feng; Spina, Valeria; Tousseyn, Thomas; Buedts, Lieselot; Hoppe, Richard; Natkunam, Yasodha; Fornecker, Luc-Matthieu; Castellino, Sharon M.; Advani, Ranjana; Rossi, Davide; Lynch, Ryan; Ghesquieres, Herve; Casasnovas, Olivier; Kurtz, David M.; Marks, Lianna J.; Link, Michael P.; Andre, Marc; Vandenberghe, Peter; Steidl, Christian; Diehn, Maximilian; Alizadeh, Ash A.
• 署名单位: Stanford University; Universite Bourgogne Europe; CHU Dijon Bourgogne; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Bourgogne Europe; Institut Agro; AgroSup Dijon; St Jude Children's Research Hospital; St Jude Children's Research Hospital; Stanford University; Stanford University; St Jude Children's Research Hospital; KU Leuven; KU Leuven; Stanford University; Institut National de la Sante et de la Recherche Medicale (Inserm); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Emory University; Children's Healthcare of Atlanta (CHOA); Institute of Oncology Research (IOR); Universita della Svizzera Italiana; Fred Hutchinson Cancer Center; CHU Lyon; Universite Catholique Louvain; KU Leuven; University Hospital Leuven
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5192
• DOI: 10.1038/s41586-023-06903-x
• 发表日期: 2024-01-25
• 关键词: circulating tumor dna; reed-sternberg cells; cancer; interleukin-13; mutations; reveals; identification; pathogenesis; landscape; genetics

摘要

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-4R alpha-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. The potential use of circulating tumour DNA in classic Hodgkin lymphoma detection, classification and monitoring is defined.