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.
Subject(s)
Circulating Tumor DNA , Genome, Human , Genomics , Hodgkin Disease , Humans , Hodgkin Disease/blood , Hodgkin Disease/classification , Hodgkin Disease/diagnosis , Hodgkin Disease/genetics , Mutation , Reed-Sternberg Cells/metabolism , Tumor Microenvironment , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Single-Cell Gene Expression Analysis , Genome, Human/geneticsABSTRACT
Understanding the tumor microenvironment and genomic landscape is crucial for better prediction of treatment outcomes and developing novel therapies in Hodgkin lymphoma (HL). Recent advancements in genomics have enabled researchers to gain deeper insights into the genomic characteristics of HL at both single-cell resolution and the whole genome level. The use of noninvasive methods such as liquid biopsies and formalin-fixed paraffin-embedded-based imaging techniques has expanded the possibilities of applying cutting-edge analyses to routine clinically available samples. Collaborative efforts between adult and pediatric group are imperative to translate novel findings into routine patient care.
