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Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

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) levels^1-4. 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.

SUBMITTER: Alig SK

PROVIDER: S-EPMC11293530 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

Alig Stefan K SK Shahrokh Esfahani Mohammad M Garofalo Andrea A Li Michael Yu MY Rossi Cédric C Flerlage Tim T Flerlage Jamie E JE Adams Ragini R Binkley Michael S MS Shukla Navika N Jin Michael C MC Olsen Mari M Telenius Adèle A Mutter Jurik A JA Schroers-Martin Joseph G JG Sworder Brian J BJ Rai Shinya S King Daniel A DA Schultz Andre A Bögeholz Jan J Su Shengqin S Kathuria Karan R KR Liu Chih Long CL Kang Xiaoman X Strohband Maya J MJ Langfitt Deanna D Pobre-Piza Kristine Faye KF Surman Sherri S Tian Feng F Spina Valeria V Tousseyn Thomas T Buedts Lieselot L Hoppe Richard R Natkunam Yasodha Y Fornecker Luc-Matthieu LM Castellino Sharon M SM Advani Ranjana R Rossi Davide D Lynch Ryan R Ghesquières Hervé H Casasnovas Olivier O Kurtz David M DM Marks Lianna J LJ Link Michael P MP André Marc M Vandenberghe Peter P Steidl Christian C Diehn Maximilian M Alizadeh Ash A AA

Nature 20231211 7996

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) levels<sup>1-4</sup>. 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 transcripti ...[more]

PMID: 38081297

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Project description:BackgroundNon-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.MethodsWe pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).ResultsRisks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.ConclusionsUsing a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

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Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

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Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

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