Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling

被引：53

作者：

Alig, Stefan K. ^{[1
]}

Shahrokh Esfahani, Mohammad ^{[1
]}

Garofalo, Andrea ^{[1
]}

Li, Michael Yu ^{[2
]}

Rossi, Cedric ^{[1
,3
,4
]}

Flerlage, Tim ^{[5
]}

Flerlage, Jamie E. ^{[6
]}

Adams, Ragini ^{[7
]}

Binkley, Michael S. ^{[8
]}

Shukla, Navika ^{[1
]}

Jin, Michael C. ^{[1
]}

Olsen, Mari ^{[1
]}

Telenius, Adele ^{[2
]}

Mutter, Jurik A. ^{[1
]}

Schroers-Martin, Joseph G. ^{[1
]}

Sworder, Brian J. ^{[1
]}

Rai, Shinya ^{[2
]}

King, Daniel A. ^{[1
]}

Schultz, Andre ^{[1
]}

Bogeholz, Jan ^{[1
]}

Su, Shengqin ^{[8
]}

Kathuria, Karan R. ^{[1
]}

Liu, Chih Long ^{[1
]}

Kang, Xiaoman ^{[1
]}

Strohband, Maya J. ^{[1
]}

Langfitt, Deanna ^{[9
]}

Pobre-Piza, Kristine Faye ^{[5
]}

Surman, Sherri ^{[5
]}

Tian, Feng ^{[1
]}

Spina, Valeria ^{[10
]}

Tousseyn, Thomas ^{[11
]}

Buedts, Lieselot ^{[12
]}

Hoppe, Richard ^{[8
]}

Natkunam, Yasodha ^{[13
]}

Fornecker, Luc-Matthieu ^{[14
,15
]}

Castellino, Sharon M. ^{[16
]}

Advani, Ranjana ^{[1
]}

Rossi, Davide ^{[17
,18
,19
]}

Lynch, Ryan ^{[20
]}

Ghesquieres, Herve ^{[21
]}

Casasnovas, Olivier ^{[3
,4
]}

Kurtz, David M. ^{[1
]}

Marks, Lianna J. ^{[7
]}

Link, Michael P. ^{[7
]}

Andre, Marc ^{[22
]}

Vandenberghe, Peter ^{[12
,23
]}

Steidl, Christian ^{[2
]}

Diehn, Maximilian ^{[8
]}

Alizadeh, Ash A. ^{[1
]}

机构：

[1] Stanford Univ, Dept Med, Div Oncol & Hematol, Stanford, CA 94305 USA

[2] British Columbia Canc, Ctr Lymphoid Canc, Vancouver, BC, Canada

[3] Univ Hosp F Mitterrand, Hematol Dept, Dijon, France

[4] Inserm UMR 1231, Dijon, France

[5] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN USA

[6] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN USA

[7] Stanford Univ, Dept Pediat, Div Hematol Oncol, Stanford, CA USA

[8] Stanford Univ, Med Ctr, Dept Radiat Oncol, Stanford, CA 94305 USA

[9] St Jude Childrens Res Hosp, Dept Bone Marrow Transplant & Cellular Therapy, Memphis, TN USA

[10] Dept Med Genet EOLAB, Lab Mol Diagnost, Bellinzona, Switzerland

[11] Univ Leuven, KU Leuven, Leuven, Belgium

[12] Dept Human Genet, KU Leuven, Leuven, Belgium

[13] Stanford Univ, Dept Pathol, Stanford, CA USA

[14] Inst Cancerol Strasbourg Europe ICANS, Strasbourg, France

[15] Univ Strasbourg, Strasbourg, France

[16] Emory Univ, Aflac Canc & Blood Disorders Ctr, Dept Pediat, Childrens Healthcare Atlanta, Atlanta, GA USA

[17] Ente Osped Cantonale, Clin Hematol, Ente Ospedaliero Cantonale, Bellinzona, Switzerland

[18] Inst Oncol Res, Lab Expt Hematol, Bellinzona, Switzerland

[19] Univ Svizzera Italiana, Fac Biomed Sci, Lugano, Switzerland

[20] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA USA

[21] Ctr Hospitalier Lyon Sud, Ctr Hosp Lyon Sud, Hosp Civils Lyon, Pierre Benite, France

[22] Catholic Univ Louvain, Dept Haematol, CHU UCL Namur, Yvoir, Belgium

[23] Univ Hosp Leuven, Dept Hematol, Leuven, Belgium

来源：

NATURE | 2024年 / 625卷 / 7996期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

CIRCULATING TUMOR DNA; REED-STERNBERG CELLS; CANCER; INTERLEUKIN-13; MUTATIONS; REVEALS; IDENTIFICATION; PATHOGENESIS; LANDSCAPE; GENETICS;

D O I：

10.1038/s41586-023-06903-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：778 / 787

页数：38

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