[en] The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n = 59) and the multicentric BREACH study by Lymphoma Study Association (n = 118). To catalog the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analyzed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25-q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13-p26 and of 12q21-q24 and gain of 15q21-q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumor volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.
Disciplines :
Hematology
Author, co-author :
Buedts, Lieselot; Department of Human Genetics and
Wlodarska, Iwona; Department of Human Genetics and
Finalet-Ferreiro, Julio; Genomics Core, KU Leuven, Leuven, Belgium
Gheysens, Olivier; Department of Nuclear Medicine and
Dehaspe, Luc; Genomics Core, KU Leuven, Leuven, Belgium
Tousseyn, Thomas; Department of Pathology, University Hospitals Leuven, Leuven, Belgium
Fornecker, Luc-Matthieu; CHU Strasbourg, Strasbourg, France
Lazarovici, Julien; Department of Hematology, Gustave Roussy and Université Paris Saclay, Villejuif, France
Casasnovas, René-Olivier; CHU Le Bocage, Dijon, France
Gac, Anne-Claire; Institute of Hematology of Lower Normandy, CHU de Caen Normandy, Normandy, France
BONNET, Christophe ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Bouabdallah, Kamal; CHU Hematology Haut-Lévêque, Pessac, France
Copie-Bergman, Christiane; Hôpital Henri Mondor, Créteil, France
Fabiani, Bettina; Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France
Dierickx, Daan; Department of Hematology, University Hospitals Leuven, Leuven, Belgium, and
Marcelis, Lukas; Department of Pathology, University Hospitals Leuven, Leuven, Belgium
Vermeesch, Joris; Department of Human Genetics and ; Genomics Core, KU Leuven, Leuven, Belgium
André, Marc; CHU UCL Namur, Namur, Belgium
Vandenberghe, Peter; Department of Human Genetics and ; Department of Hematology, University Hospitals Leuven, Leuven, Belgium, and
The landscape of copy number variations in classical Hodgkin lymphoma: a joint KU Leuven and LYSA study on cell-free DNA.
Publication date :
2021
Journal title :
Blood Advances
ISSN :
2473-9529
eISSN :
2473-9537
Publisher :
American Society of Hematology, United States
Volume :
5
Pages :
1991-2002
Peer reviewed :
Peer Reviewed verified by ORBi
Funding text :
This study was supported by grants of the Research Foundation Flanders (FWO) G0A1116N (I.W. and P.V.) and the Foundation Against Cancer (STK) FAF-C/2016/836 (P.V.).
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