1. Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma
- Author
-
Kristin Hartung, Carl Friedrich Classen, Dirk Reinhardt, Mathias J. Rummel, Stefan Burdach, Harald Reinhard, Alexander Brobeil, Andreas E. Kulozik, Roland Schmitz, Stefan S. Bielack, Arnulf Pekrun, Christian Flotho, Hermann L. Müller, Udo Kontny, Thorsten Simon, Karl-Walter Sykora, Christof M. Kramm, Michael Paulussen, Thomas Georgi, Ann-Kathrin Desch, Michaela Nathrath, Claudia Rossig, Norbert Graf, Stefan Gattenlöhner, Paul-Gerhardt Schlegel, Peter Vorwerk, Lars Kurch, Michael C. Frühwald, Ante Botzen, Meinolf Suttorp, Klaus-Michael Debatin, Thomas Nüßlein, Andreas Bräuninger, Lothar Schweigerer, Alexander Claviez, Markus Metzler, Joachim Kühr, Norbert Jorch, Dominik T. Schneider, Martin Ebinger, Axel Sauerbrey, Angelika Eggert, Wolfram Scheurlen, Jörg Faber, Regine Kluge, C Mauz-Körholz, Dieter Körholz, and Theresa Jox
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Adolescent ,Genotype ,Antigen presentation ,Medizin ,Chromosomal translocation ,Biology ,Circulating Tumor DNA ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Child ,Gene ,Allele frequency ,Genotyping ,Breakpoint ,Germinal center ,Hematology ,Hodgkin Disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Child, Preschool ,Cancer research ,Female - Abstract
We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.
- Published
- 2020