A comprehensive genetic study of classic Hodgkin lymphoma using circulating tumor DNA
Abstract
Abstract This study analyzed the genetics of classic Hodgkin lymphoma (cHL) by using circulating tumor DNA (ctDNA). Two genetic subtypes were identified, differing in genetic instability mechanisms: one subtype (64% of cases) showed a higher mutation load and a higher fraction of mutations associated with activation-induced cytidine deaminase and microsatellite instability signatures, whereas the other subtype (36% of cases) exhibited chromosomal instability with more somatic copy number alterations. Whole-genome duplication was more common in cHL compared with other B-cell tumors and emerged as a prognostic biomarker for patients undergoing Adriamycin (doxorubicin)-bleomycin-vinblastine-dacarbazine–based therapy. Noncoding regulatory mutations, similar to those in diffuse large B-cell lymphoma, were highly prevalent in 86% of cHL. A recurrent somatic expression quantitative trait locus (seQTL) involving the BCL6 gene was found in 30% of cases. The seQTL of BCL6 aligned with accessible chromatin and increased H3K27 acetylation in cHL, disrupted PRDM1 binding, and co-occurred with BCL6 expression in cHL cells. Weak to strong expression of BCL6 was observed in 68% of cases, and BCL6 expression associated with gene repression similarly in cHL and germinal center B cells. After BCL6 degradation, the core set of genes directly bound and regulated by BCL6 was derepressed in cHL, and proliferation was impaired. The number and clonality of neoantigens was associated with tumor microenvironment type and response to checkpoint blockade. Finally, ctDNA analysis was suggested as a tool to distinguish ambiguous positron emission tomography/computed tomography–positive lesions after treatment.
Article Details
Authors (52)
Maria Cristina Pirosa
1Clinic of Hematology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
Alessio Bruscaggin
Institute of Oncology Research, Bellinzona, Switzerland
Lodovico Terzi di Bergamo
Institute of Oncology Research, Bellinzona, Switzerland
Matin Salehi
3Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
Federico Jauk
4Institute of Oncology Research, Bellinzona, Switzerland
Gabriela Forestieri
Institute of Oncology Research, Bellinzona, Switzerland
Simone Bocchetta
1Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
Deborah Piffaretti
1Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
Riccardo Moia
32Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
Vanessa Cristaldi
7Department of Biomedical Sciences, Humanitas University, Milan, Italy
Martina di Trani
7Department of Biomedical Sciences, Humanitas University, Milan, Italy
Georgia Alice Galimberti
1Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
Katia Pini
1Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
Valeria Spina
1Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
Claudia Giordano
8Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
Adalgisa Condoluci
1Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
Ilaria Romano
37Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Salvatore Annunziata
9UOC Medicina Nucleare, GSTeP Radiopharmacy TracerGLab, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Fabrizio Bergesio
2Santa Croce e Carle General Hospital, Cuneo, Italy
Renzo Boldorini
11Pathology Department, Ospedale Maggiore della Carità, University of Eastern Piedmont, Novara, Italy
Eugenio Borsatti
12Nuclear Medicine, Centro di Riferimento Oncologico, Aviano, Italy
Pietro Bulian
13Clinical and Experimental Onco Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy
Eleonora Calabretta
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
Stephane Chauvie
2Santa Croce e Carle General Hospital, Cuneo, Italy
Francesco Corrado
9Center for Early Detection and Interception, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Stefania Crisci
14Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori-IRCCS-Fondazione “G. Pascale,” Naples, Italy
Marco Cuzzocrea
15Clinic of Nuclear Medicine and Molecular Imaging, Imaging Institute of Southern Switzerland, Bellinzona, Switzerland
Rosaria De Filippi
8Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy
Bernhard Gerber
2Clinic of Hematology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
Michał Kurlapski
16Department of Hematology and Bone Marrow Transplantation, Medical University of Gdańsk, Gdańsk, Poland
Luigi Maria Larocca
17Division of Pathology, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of the Sacred Heart, Rome, Italy
Elisabetta Merlo
18Division of Pathology, Ente Ospedaliero Cantonale, Locarno, Switzerland
Andrea Rinaldi
Marcello Rodari
20Unit of Nuclear Medicine, Humanitas Research Hospital, Milan, Italy
Grzegorz Romanowicz
21Department of Nuclear Medicine, Medical University of Gdańsk, Gdańsk, Poland
Gian Mauro Sacchetti
22Nuclear Medicine, Ospedale Maggiore della Carità, Novara, Italy
Anastasios Stathis
Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzoona, Switzerland
Georg Stussi
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Ilaria Zangrilli
23Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
Antonello Pinto
15Istituto Nazionale Tumori, IRCCS-Fondazione “G. Pascale”, Naples, Italy
Luca Mazzucchelli
Ente Ospedaliero Cantonale, Istituto Cantonale di Patologia
Valter Gattei
3Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
Jan Maciej Zaucha
Armando Santoro
IRCCS Humanitas Research Hospital, Milan
Stefan Hohaus
14Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Franco Cavalli
2Institute of Oncology Research, Bellinzona, Switzerland
Alexandar Tzankov
Carmelo Carlo-Stella
3Humanitas University and IRCCS Humanitas Research Hospital, Milan, Italy
Gianluca Gaidano
13Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
Luca Ceriani
2Institute of Oncology Research, Bellinzona, Switzerland
Emanuele Zucca
Institute of Oncology Research, Bellinzona, Switzerland
Davide Rossi
Institute of Oncology Research, Bellinzona, Switzerland