Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

Alig, Stefan K Esfahani, Mohammad Shahrokh Garofalo, Andrea Li, Michael Yu Rossi, Cédric Flerlage, Tim Flerlage, Jamie E Adams, Ragini Binkley, Michael S Shukla, Navika Jin, Michael C Olsen, Mari Telenius, Adèle Mutter, Jurik A Schroers-Martin, Joseph G Sworder, Brian J Rai, Shinya King, Daniel A Schultz, Andre Bögeholz, 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 Ghesquières, Hervé Casasnovas, Olivier Kurtz, David M Marks, Lianna J Link, Michael P André, Marc [UCL] Vandenberghe, Peter Steidl, Christian Diehn, Maximilian Alizadeh, Ash A et al.[show all]

The scarcity of malignant Hodgkin and Reed-Sternberg (HRS) cells hamper tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). Liquid biopsies, in contrast, show promise for molecular profiling of cHL due to relatively high circulating tumor DNA (ctDNA) levels. Here, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate HRS ctDNA shedding to be shaped by DNASE1L3, whose increased tumor 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 IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, using PhasED-Seq we demonstrate the clinical value of pre- 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.