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Non Hodgkin-Lymphoma
Shallow-depth sequencing of cell-free DNA for Hodgkin and diffuse large B-cell lymphoma (differential) diagnosis: a standardized approach with underappreciated potential
Lennart Raman,1,2,* Malaïka Van der Linden,1,2,* Ciel De Vriendt,3,* Bliede Van den Broeck,4 Kristoff Muylle,5 Dries Deeren,6 Franceska Dedeurwaerdere,7 Sofie Verbeke,1 Amélie Dendooven,1,8 Katrien De Grove,3 Saskia Baert,3 Kathleen Claes,2 Björn Menten,2 Fritz Offner3# and Jo Van Dorpe1#
1Department of Pathology, Ghent University, Ghent University Hospital, Ghent; 2Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent University Hospital, Ghent; 3Department of Clinical Hematology, Ghent University, Ghent University Hospital, Ghent; 4Department of Nuclear Medicine, Ghent University, Ghent University Hospital, Ghent; 5Department of Nuclear Medicine, AZ Delta, Roeselare; 6Department of Hematology, AZ Delta, Roeselare; 7Deparment of Pathology, AZ Delta, Roeselare and 8Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
*LR, MVDL and CDV contributed equally as co-first authors. #JVD and FO contributed equally as co-senior authors.
ABSTRACT
Shallow-depth sequencing of cell-free DNA, an inexpensive and standardized approach to obtain molecular information on tumors non-invasively, has been insufficiently explored for the diagnosis of lymphoma and disease follow-up. This study collected 318 samples, including longitudinal liquid and paired solid biopsies, from a prospec- tively-recruited cohort of 38 Hodgkin lymphoma (HL) and 85 aggressive B-cell non-HL patients, represented by 81 diffuse large B-cell lymphoma (DLBCL) cases. Following sequencing, copy number alterations and viral read fractions were derived and analyzed. At diagnosis, liquid biopsies showed detectable copy number alterations in 84.2% of HL patients (88.6% for classical HL) and 74.1% of DLBCL patients. Of the DLBCL patients, copy number profiles between liquid-solid pairs were highly concordant (r=0.815±0.043); and, compared to tissue, HL liquid biopsies had abnormalities with higher amplitudes (P=0.010). This implies that tumor DNA is more abundant in plasma. Additionally, 39.5% of HL and 13.6% of DLBCL cases had a significantly elevated number of plasma Epstein-Barr virus DNA fragments, achieving a sensitivity of 100% com- pared to the current standard. A longitudinal analysis determined that, when detectable, copy number patterns were similar across (re)staging moments in refractory or relapsed patients. Further, the overall profile anomaly correlated highly with the total metabolic tumor volume (P<0.001). To conclude, as a proof of principle, we demonstrate that liq- uid biopsy-derived copy numbers can aid diagnosis: e.g., by differentiat- ing HL from DLBCL, random forest modeling is represented by an area under the receiver operating characteristic curve of 0.967. This applica- tion is potentially useful when tissue is difficult to obtain or when biop- sies are small and inconclusive.
Introduction
B-cell-derived lymphomas can develop at different stages along the B-lymphocyte differentiation pathways. This generates a range of tumor entities1 including Hodgkin lymphoma (HL) as well as diverse non-HL (nHL) varieties, with diffuse large B-cell lymphoma (DLBCL) the most common nHL.
Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):211-220
Correspondence:
JO VAN DORPE
Jo.VanDorpe@uzgent.be
Received: August 3, 2020. Accepted: November 25, 2020. Pre-published: December 10, 2020.
https://doi.org/10.3324/haematol.2020.268813 ©2022 Ferrata Storti Foundation
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